72 results on '"La Pietra, V"'
Search Results
2. Exploring the N-Terminal Region of C-X-C Motif Chemokine 12 (CXCL12)
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Di Maro S., Trotta A.M., Brancaccio D., Di Leva F.S., La Pietra V., Ierano C., Napolitano M., Portella L., D'Alterio C., Siciliano R.A., Sementa D., Tomassi S., Carotenuto A., Novellino E., Scala S., and Marinelli L.
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PHARMACOKINETICS ,Chemokine - Abstract
We previously reported the discovery of a CXCL12-mimetic cyclic peptide (2) as a selective CXCR4 antagonist showing promising in vitro and in vivo anticancer activity. However, further development of this peptide was hampered by its degradation in biological fluids as well as by its low micromolar affinity for the receptor. Herein, extensive chemical modifications led to the development of a new analogue (10) with enhanced potency, specificity, and plasma stability. A combined approach of Ala-amino acid scan, NMR, and molecular modeling unraveled the reasons behind the improved binding properties of 10 vs 2. Biological investigations on leukemia (CEM) and colon (HT29 and HCT116) cancer cell lines showed that 10 is able to impair CXCL12-mediated cell migration, ERK-phosphorylation, and CXCR4 internalization. These outcomes might pave the way for the future preclinical development of 10 in CXCR4 overexpressing leukemia and colon cancer.
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- 2016
3. NMR structure of peptide 2 targeting CXCR4
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Di Maro, S., primary, Trotta, A.M., additional, Brancaccio, D., additional, Di Leva, F.S., additional, La Pietra, V., additional, Ierano, C., additional, Napolitano, M., additional, Portella, L., additional, D'Alterio, C., additional, Siciliano, R.A., additional, Sementa, D., additional, Tomassi, S., additional, Carotenuto, A., additional, Novellino, E., additional, Scala, S., additional, and Marinelli, L., additional
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- 2016
- Full Text
- View/download PDF
4. NMR structure of peptide 10 targeting CXCR4
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Di Maro, S., primary, Trotta, A.M., additional, Brancaccio, D., additional, Di Leva, F.S., additional, La Pietra, V., additional, Ierano, C., additional, Napolitano, M., additional, Portella, L., additional, D'Alterio, C., additional, Siciliano, R.A., additional, Sementa, D., additional, Tomassi, S., additional, Carotenuto, A., additional, Novellino, E., additional, Scala, S., additional, and Marinelli, L., additional
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- 2016
- Full Text
- View/download PDF
5. Glioblastoma multiforme: induction of mitochondria-mediated apoptotic pathway by simultaneous pharmacological activation of TSPO (18KDa) and p53
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Claudia Martini, Eleonora Da Pozzo, BARBARA COSTA, Simona Daniele, Chiara Giacomelli, Maria Letizia Trincavelli, SABRINA TALIANI, Elisabetta Barresi, FEDERICO DA SETTIMO PASSETTI, Carotenuto, A., Limatola, A., Lamberti, A., La Pietra, V., Marinelli, L., and Novellino, E.
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- 2013
6. Drug design and synthesis of GSK-3β inhibitors
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Famiglini, Valeria, Bordoni, C., La Pietra, V., LA REGINA, Giuseppe, Coluccia, Antonio, Pelliccia, S., Plotkin, B., Eldar Finkelman, H., Brancale, A., Marinelli, L., Novellino, E., and Silvestri, Romano
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- 2013
7. Indole-based modulators of p53/MDM2 interaction as antitumoral agents
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Elisabetta Barresi, Pugliesi, I., SABRINA TALIANI, FEDERICO DA SETTIMO PASSETTI, La Pietra, V., Marinelli, L., Novellino, E., Baratta, C., Eleonora Da Pozzo, BARBARA COSTA, and Claudia Martini
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- 2012
8. NOVEL KINASE INHIBITORS IN THYROID CANCER TREATMENT: SYNTHESIS AND BIOLOGICAL EVALUATION
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Sartini, S, Landi, A, Salerno, Silvia, Simorini, Francesca, Taliani, Sabrina, Marini, ANNA MARIA, LA MOTTA, Concettina, DA SETTIMO PASSETTI, Federico, Antonelli, A, Bocci, Guido, La Pietra, V, Marinelli, L, and Novellino, E.
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- 2012
9. Novel Pyrazolopyrimidine Derivatives as Therapeutic Agents for the Treatment of Medullary Thyroid Carcinoma
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Sartini, S., Morelli, M., Patti, A., Simorini, Francesca, Taliani, Sabrina, Salerno, Silvia, Marini, ANNA MARIA, Cosconati, S., La Pietra, V., Marinelli, L., Fioravanti, A., Di Desidero, T., Bocci, Guido, Ferrari, S. M., Fallahi, P., Antonelli, A., LA MOTTA, Concettina, DA SETTIMO PASSETTI, Federico, and Novellino, E.
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- 2011
10. Lead optimization of a novel molecular scaffold in search for novel MMP-13 inhibitors
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Taliani, Sabrina, Pugliesi, I., Barresi, Elisabetta, Simorini, Francesca, Salerno, Silvia, LA MOTTA, Concettina, Marini, ANNA MARIA, Nuti, Elisa, La Pietra, V., Cosconati, S., Marinelli, L., Rossello, Armando, DA SETTIMO PASSETTI, Federico, and Novellino, E.
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- 2010
11. Benzo[d]isothiazoles and Matrix Metalloproteinases. Searching for Novel and Selective Inhibitors of MMP9
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LA MOTTA, Concettina, Sartini, S., Salerno, Silvia, Simorini, Francesca, Taliani, Sabrina, Marini, ANNA MARIA, DA SETTIMO PASSETTI, Federico, Nuti, Elisa, Santamaria, S., Rossello, Armando, Marinelli, L., LA PIETRA, V., and Novellino, E.
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- 2008
12. Indole-based modulators of p53/MDM2 interaction as antitumoral agents
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Elisabetta Barresi, Pugliesi, I., SABRINA TALIANI, FEDERICO DA SETTIMO PASSETTI, Carotenuto, A., Limatola, A., Lamberti, A., La Pietra, V., Marinelli, L., Novellino, E., Simona Daniele, Eleonora Da Pozzo, BARBARA COSTA, and Claudia Martini
13. Discovery of the First-in-Class GSK-3β/HDAC Dual Inhibitor as Disease-Modifying Agent To Combat Alzheimer’s Disease
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Deborah Pietrobono, Nicola Petragnani, Vincenza Andrisano, Claudia Martini, Vincenzo Tumiatti, Nibal Betari, Serena Montanari, Simona Daniele, Lara Davani, Angela Nebbioso, Ettore Novellino, F. Frabetti, Barbara Monti, Pasquale Russomanno, Angela De Simone, Andrea Milelli, Federica Sarno, Lucia Altucci, Patrizia Ballerini, Raffaella Casadei, Valeria La Pietra, Mariarosaria Conte, Sabrina Petralla, De Simone, Angela, La Pietra, Valeria, Betari, Nibal, Petragnani, Nicola, Conte, Mariarosaria, Daniele, Simona, Pietrobono, Deborah, Martini, Claudia, Petralla, Sabrina, Casadei, Raffaella, Davani, Lara, Frabetti, Flavia, Russomanno, Pasquale, Novellino, Ettore, Montanari, Serena, Tumiatti, Vincenzo, Ballerini, Patrizia, Sarno, Federica, Nebbioso, Angela, Altucci, Lucia, Monti, Barbara, Andrisano, Vincenza, Milelli, Andrea, De Simone A, La Pietra V, Betari N, Petragnani N, Conte M, Daniele S, Pietrobono D, Martini C, Petralla S, Casadei R, Davani L, Frabetti F, Russomanno P, Novellino E, Montanari S, Tumiatti V, Ballerini P, Sarno F, Nebbioso A, Altucci L, Monti B, Andrisano V, Milelli A., De Simone, A., La Pietra, V., Betari, N., Petragnani, N., Conte, M., Daniele, S., Pietrobono, D., Martini, C., Petralla, S., Casadei, R., D'Avani, Paolo, Frabetti, F., Novellino, E., Montanari, S., Tumiatti, V., Ballerini, P., Sarno, F., Nebbioso, A., Altucci, L., Monti, B., Andrisano, ANGELA-MARIA, and Milelli, A.
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dual binding agents ,Polypharmacology, epigenetics, dual binding agents, glycogen synthase kinase 3β, histone deacetylases, neuroprotection ,Polypharmacology ,Disease ,01 natural sciences ,Biochemistry ,Neuroprotection ,GSK-3 ,Drug Discovery ,Epigenetics ,epigenetics ,glycogen synthase kinase 3β ,histone deacetylases ,neuroprotection ,biology ,010405 organic chemistry ,Chemistry ,Drug Discovery3003 Pharmaceutical Science ,Organic Chemistry ,Neurogenesis ,0104 chemical sciences ,Cell biology ,010404 medicinal & biomolecular chemistry ,Histone ,Cell culture ,Acetylation ,dual binding agent ,histone deacetylase ,biology.protein ,epigenetic - Abstract
[Image: see text] Several evidence pointed out the role of epigenetics in Alzheimer’s disease (AD) revealing strictly relationships between epigenetic and “classical” AD targets. Based on the reported connection among histone deacetylases (HDACs) and glycogen synthase kinase 3β (GSK-3β), herein we present the discovery and the biochemical characterization of the first-in-class hit compound able to exert promising anti-AD effects by modulating the targeted proteins in the low micromolar range of concentration. Compound 11 induces an increase in histone acetylation and a reduction of tau phosphorylation. It is nontoxic and protective against H(2)O(2) and 6-OHDA stimuli in SH-SY5Y and in CGN cell lines, respectively. Moreover, it promotes neurogenesis and displays immunomodulatory effects. Compound 11 shows no lethality in a wt-zebrafish model (
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- 2019
14. Protein Flexibility in Virtual Screening: The BACE-1 Case Study
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Vincenza Andrisano, Valeria La Pietra, David S. Goodsell, Angela De Simone, Sandro Cosconati, Luciana Marinelli, Francesca Mancini, Arthur J. Olson, Ettore Novellino, Francesco Saverio Di Leva, S., Cosconati, Marinelli, Luciana, Di Leva, Francesco Saverio, LA PIETRA, Valeria, A., De Simone, F., Mancini, V., Andrisano, Novellino, Ettore, D. S., Goodsell, A. J., Olson, Cosconati S., Marinelli L., Di Leva F.S., La Pietra V., De Simone A., Mancini F., Andrisano V., Novellino E., Goodsell D.S., Olson A.J., Cosconati, Sandro, Marinelli, L, Di Leva, F, La Pietra, V, De Simone, A, Mancini, F, Andrisano, V, Novellino, E, Goodsell, D, and Olson, A. J.
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STRUCTURE-BASED DESIGN ,FLEXIBLE SIDE-CHAINS ,MEMAPSIN-2 BETA-SECRETASE ,APP CLEAVING ENZYME ,DRUG DESIGN ,MOLECULAR RECOGNITION ,ALZHEIMERS-DISEASE ,LIGAND DOCKING ,SOFT DOCKING ,ACTIVE-SITE ,Protein Conformation ,General Chemical Engineering ,Library and Information Sciences ,Machine learning ,computer.software_genre ,Crystallography, X-Ray ,Ligands ,Molecular Docking Simulation ,Article ,Antiparkinson Agents ,User-Computer Interface ,Alzheimer Disease ,High-Throughput Screening Assays ,Drug Discovery ,Fluorescence Resonance Energy Transfer ,Aspartic Acid Endopeptidases ,Humans ,Simulation ,Virtual screening ,Binding Sites ,Chemistry ,business.industry ,Drug discovery ,General Chemistry ,Grid ,Computer Science Applications ,Weighting ,Thermodynamics ,Artificial intelligence ,Amyloid Precursor Protein Secretases ,business ,computer ,Algorithms ,Databases, Chemical ,Protein Binding - Abstract
Simulating protein flexibility is a major issue in the docking-based drug-design process for which a single methodological solution does not exist. In our search of new anti-Alzheimer ligands, we were faced with the challenge of including receptor plasticity in a virtual screening campaign aimed at finding new β-secretase inhibitors. To this aim, we incorporated protein flexibility in our simulations by using an ensemble of static X-ray enzyme structures to screen the National Cancer Institute database. A unified description of the protein motion was also generated by computing and combining a set of grid maps using an energy weighting scheme. Such a description was used in an energy-weighted virtual screening experiment on the same molecular database. Assessment of the enrichment factors from these two virtual screening approaches demonstrated comparable predictive powers, with the energy-weighted method being faster than the ensemble method. The in vitro evaluation demonstrated that out of the 32 tested ligands, 17 featured the predicted enzyme inhibiting property. Such an impressive success rate (53.1%) demonstrates the enhanced power of the two methodologies and suggests that energy-weighted virtual screening is a more than valid alternative to ensemble virtual screening given its reduced computational demands and comparable performance. © 2012 American Chemical Society.
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- 2012
15. Interfering with the Tumor-Immune Interface: Making Way for Triazine-Based Small Molecules as Novel PD-L1 Inhibitors
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Linda Cerofolini, Gerolama Condorelli, Giovanna Polcaro, Daniela Arosio, Vincenzo Maria D'Amore, Stefano Pepe, Riccardo Scaglia, Marco Fragai, E. Novellino, Giulia Assoni, Luciana Marinelli, Pasquale Russomanno, Stefano Giuntini, Jussara Amato, Diego Brancaccio, Francesco Sabbatino, Marianna Falzoni, Valeria La Pietra, Greta Donati, Paolo Orlando, Pierfausto Seneci, Cristina Quintavalle, Martina Pedrini, Bruno Pagano, Russomanno, P., Assoni, G., Amato, J., D'Amore, V. M., Scaglia, R., Brancaccio, D., Pedrini, M., Polcaro, G., La Pietra, V., Orlando, P., Falzoni, M., Cerofolini, L., Giuntini, S., Fragai, M., Pagano, B., Donati, G., Novellino, E., Quintavalle, C., Condorelli, G., Sabbatino, F., Seneci, P., Arosio, D., Pepe, S., and Marinelli, L.
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Models, Molecular ,medicine.drug_class ,Immune Checkpoint Inhibitor ,B7-H1 Antigen ,Calorimetry, Differential Scanning ,Cell Line, Tumor ,Coculture Techniques ,Humans ,Immune Checkpoint Inhibitors ,Neoplasms ,Small Molecule Libraries ,Structure-Activity Relationship ,Triazines ,Calorimetry ,Monoclonal antibody ,Differential Scanning ,Peripheral blood mononuclear cell ,PD-1/PD-L1 ,Cell Line ,03 medical and health sciences ,0302 clinical medicine ,Immune system ,Small Molecule Librarie ,Models ,PD-L1 ,Drug Discovery ,medicine ,Cytotoxicity ,Coculture Technique ,immune checkpoint ,030304 developmental biology ,0303 health sciences ,Tumor ,biology ,Chemistry ,Molecular ,Small molecule ,3. Good health ,Triazine ,Apoptosis ,030220 oncology & carcinogenesis ,Cancer cell ,Cancer research ,biology.protein ,Molecular Medicine ,Neoplasm ,Human - Abstract
The inhibition of the PD-1/PD-L1 axis by monoclonal antibodies has achieved remarkable success in treating a growing number of cancers. However, a novel class of small organic molecules, with BMS-202 (1) as the lead, is emerging as direct PD-L1 inhibitors. Herein, we report a series of 2,4,6-tri- and 2,4-disubstituted 1,3,5-triazines, which were synthesized and assayed for their PD-L1 binding by NMR and homogeneous time-resolved fluorescence. Among them, compound 10 demonstrated to strongly bind with the PD-L1 protein and challenged it in a co-culture of PD-L1 expressing cancer cells (PC9 and HCC827 cells) and peripheral blood mononuclear cells enhanced antitumor immune activity of the latter. Compound 10 significantly increased interferon γ release and apoptotic induction of cancer cells, with low cytotoxicity in healthy cells when compared to 1, thus paving the way for subsequent preclinical optimization and medical applications.
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- 2021
16. CXCR4 antagonism sensitizes cancer cells to novel indole-based MDM2/4 inhibitors in glioblastoma multiforme
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Claudia Martini, Valeria La Pietra, Romano Silvestri, Linda Cerofolini, Simona Daniele, Michela Puxeddu, Sabrina Taliani, Chiara Cavallini, Martina Pedrini, Stefano Giuntini, Marianna Nalli, Vincenzo Maria D'Amore, Luciana Marinelli, Marco Fragai, Claudio Luchinat, Ettore Novellino, Deborah Pietrobono, Rebecca Piccarducci, Giuseppe La Regina, Pasquale Russomanno, Daniele, S., La Pietra, V., Piccarducci, R., Pietrobono, D., Cavallini, C., D'Amore, V. M., Cerofolini, L., Giuntini, S., Russomanno, P., Puxeddu, M., Nalli, M., Pedrini, M., Fragai, M., Luchinat, C., Novellino, E., Taliani, S., La Regina, G., Silvestri, R., Martini, C., and Marinelli, L.
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0301 basic medicine ,p53 ,Benzylamines ,Indoles ,Cell Cycle Proteins ,Cyclams ,CXCR4 ,Benzylamine ,0302 clinical medicine ,Cell Movement ,Cell Cycle Protein ,Antineoplastic Combined Chemotherapy Protocols ,Proto-Oncogene Protein ,CXCR4 antagonist ,biology ,Chemistry ,GBM stem-Like cells (GSCs) ,Brain Neoplasms ,Drug Synergism ,Proto-Oncogene Proteins c-mdm2 ,Cyclam ,Neoplastic Stem Cells ,Mdm2 ,Stem cell ,Human ,Signal Transduction ,Receptors, CXCR4 ,Neurogenesis ,Brain Neoplasm ,03 medical and health sciences ,MDM4 ,Downregulation and upregulation ,MDM2 ,Glioma ,Neurosphere ,Cell Line, Tumor ,Proto-Oncogene Proteins ,Spheroids, Cellular ,medicine ,Humans ,Neoplasm Invasiveness ,Cell Proliferation ,Pharmacology ,Neoplasm Invasivene ,Glioblastoma multiforme (GBM) ,Antineoplastic Combined Chemotherapy Protocol ,medicine.disease ,030104 developmental biology ,Indole ,Cancer cell ,biology.protein ,Cancer research ,Neurogenesi ,Neoplastic Stem Cell ,Tumor Suppressor Protein p53 ,Glioblastoma ,030217 neurology & neurosurgery - Abstract
Glioblastoma Multiforme (GBM) is a highly invasive primary brain tumour characterized by chemo- and radio-resistance and poor overall survival. GBM can present an aberrant functionality of p53, caused by the overexpression of the murine double minute 2 protein (MDM2) and its analogue MDM4, which may influence the response to conventional therapies. Moreover, tumour resistance/invasiveness has been recently attributed to an overexpression of the chemokine receptor CXCR4, identified as a pivotal mediator of glioma neovascularization. Notably, CXCR4 and MDM2-4 cooperate in promoting tumour invasion and progression. Although CXCR4 actively promotes MDM2 activation leading to p53 inactivation, MDM2-4 knockdown induces the downregulation of CXCR4 gene transcription. Our study aimed to assess if the CXCR4 signal blockade could enhance glioma cells' sensitivity to the inhibition of the p53-MDMs axis. Rationally designed inhibitors of MDM2/4 were combined with the CXCR4 antagonist, AMD3100, in human GBM cells and GBM stem-like cells (neurospheres), which are crucial for tumour recurrence and chemotherapy resistance. The dual MDM2/4 inhibitor RS3594 and the CXCR4 antagonist AMD3100 reduced GBM cell invasiveness and migration in single-agent treatment and mainly in combination. AMD3100 sensitized GBM cells to the antiproliferative activity of RS3594. It is noteworthy that these two compounds present synergic effects on cancer stem components: RS3594 inhibited the growth and formation of neurospheres, AMD3100 induced differentiation of neurospheres while enhancing RS3594 effectiveness preventing their proliferation/clonogenicity. These results confirm that blocking CXCR4/MDM2/4 represents a valuable strategy to reduce GBM proliferation and invasiveness, acting on the stem cell component too.
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- 2020
17. Enriching the Arsenal of Pharmacological Tools against MICAL2
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Ivana Barravecchia, Elisabetta Barresi, Camilla Russo, Francesca Scebba, Chiara De Cesari, Valerio Mignucci, Davide De Luca, Silvia Salerno, Valeria La Pietra, Mariateresa Giustiniano, Sveva Pelliccia, Diego Brancaccio, Greta Donati, Federico Da Settimo, Sabrina Taliani, Debora Angeloni, Luciana Marinelli, Barravecchia, I., Barresi, E., Russo, C., Scebba, F., De Cesari, C., Mignucci, V., De Luca, D., Salerno, S., La Pietra, V., Giustiniano, M., Pelliccia, S., Brancaccio, D., Donati, G., Da Settimo, F., Taliani, S., Angeloni, D., and Marinelli, L.
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Passerini-like 3-CR ,Multicomponent reactions (MCRs) ,Pharmaceutical Science ,CCG-1423 ,MICAL2 ,wound healing assay ,HMEC-1 endothelial cells ,786-O kidney cancer cells ,metastasis ,neoangiogenesis ,multicomponent reactions (MCRs) ,Passerini 3-CR reaction ,Metastasi ,Article ,Analytical Chemistry ,HMEC-1 endothelial cell ,Small Molecule Libraries ,Metastasis ,Neoangiogenesis ,Wound healing assay ,QD241-441 ,Drug Discovery ,Humans ,Enzyme Inhibitor ,Anilides ,Enzyme Inhibitors ,Physical and Theoretical Chemistry ,Molecular Structure ,Microfilament Proteins ,Organic Chemistry ,Microfilament Protein ,Neoangiogenesi ,786-O kidney cancer cell ,Oxidoreductase ,Chemistry (miscellaneous) ,Benzamides ,Molecular Medicine ,Oxidoreductases ,Human - Abstract
Molecule interacting with CasL 2 (MICAL2), a cytoskeleton dynamics regulator, are strongly expressed in several human cancer types, especially at the invasive front, in metastasizing cancer cells and in the neo-angiogenic vasculature. Although a plethora of data exist and stress a growing relevance of MICAL2 to human cancer, it is worth noting that only one small-molecule inhibitor, named CCG-1423 (1), is known to date. Herein, with the aim to develop novel MICAL2 inhibitors, starting from CCG-1423 (1), a small library of new compounds was synthetized and biologically evaluated on human dermal microvascular endothelial cells (HMEC-1) and on renal cell adenocarcinoma (786-O) cells. Among the novel compounds, 10 and 7 gave interesting results in terms of reduction in cell proliferation and/or motility, whereas no effects were observed in MICAL2-knocked down cells. Aside from the interesting biological activities, this work provides the first structure–activity relationships (SARs) of CCG-1423 (1), thus providing precious information for the discovery of new MICAL2 inhibitors.
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- 2021
18. Design, synthesis and biological evaluation of novel TRβ selective agonists sustained by ADME-toxicity analysis
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Amedeo Columbano, Grazia Chiellini, Luciana Marinelli, Ettore Novellino, Vincenzo Maria D'Amore, Marta Anna Kowalik, Massimiliano Runfola, Valeria La Pietra, Sheraz Gul, Lorenza Bellusci, Andrea Perra, Simona Sestito, Simona Rapposelli, Runfola, M., Sestito, S., Bellusci, L., La Pietra, V., D'Amore, V. M., Kowalik, M. A., Chiellini, G., Gul, S., Perra, A., Columbano, A., Marinelli, L., Novellino, E., and Rapposelli, S.
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Male ,Thyronamine ,Hep G2 Cell ,Fatty-liver disorder ,Liver regeneration ,TRβ selective agonist ,Triiodothyronine ,Pharmacology ,01 natural sciences ,Thyroid hormone receptor beta ,03 medical and health sciences ,chemistry.chemical_compound ,Structure-Activity Relationship ,Drug Discovery ,Animals ,Humans ,Uracil ,030304 developmental biology ,ADME ,0303 health sciences ,Thyroid hormone receptor ,Dose-Response Relationship, Drug ,Molecular Structure ,010405 organic chemistry ,Drug discovery ,Animal ,Organic Chemistry ,Lipid metabolism ,Thyroid Hormone Receptors beta ,General Medicine ,Hep G2 Cells ,Rats, Inbred F344 ,0104 chemical sciences ,Rats ,Pyridazines ,chemistry ,Drug Design ,Toxicity ,Rat ,Pyridazine ,Human - Abstract
Although triiodothyronine (T3) induces several beneficial effects on lipid metabolism, its use is hampered by toxic side-effects, such as tachycardia, arrhythmia, heart failure, bone and muscle catabolism and mood disturbances. Since the α isoform of thyroid hormone receptors (TRs) is the main cause of T3-related harmful effects, several efforts have been made to develop selective agonists of the β isoform that could induce some beneficial effects (i.e. lowering triglyceride and cholesterol levels reducing obesity and improving metabolic syndrome), while overcoming most of the adverse T3-dependent side effects. Herein, we describe the drug discovery process sustained by ADME-Toxicity analysis that led us to identify novel agonists with selectivity for the isoform TRβ and an acceptable off-target and absorption, distribution metabolism, excretion and toxicity (ADME-Tox) profile. Within the small series of compounds synthesized, derivatives 1 and 3, emerge from this analysis as “potentially safe” to be engaged in preclinical studies. In in vitro investigation proved that both compounds were able to reduce lipid accumulation in HepG2 and promote lipolysis with comparable effects to those elicited by T3, used as reference drug. Moreover, a preliminary in vivo study confirmed the apparent lack of toxicity, thus suggesting compounds 1 and 3 as new potential TRβ-selective thyromimetics.
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- 2019
19. Identification of novel molecular scaffolds for the design of MMP-13 inhibitors: A first round of lead optimization
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Valeria La Pietra, Sabrina Taliani, Hideaki Nagase, Elisa Nuti, Robert Visse, Federico Da Settimo, Francesco Saverio Di Leva, Ettore Novellino, Luciana Marinelli, Concettina La Motta, Salvatore Santamaria, Sandro Cosconati, Matteo Morelli, Armando Rossello, F Casalini, Isabella Pugliesi, La Pietra, V, Marinelli, L, Cosconati, Sandro, Di Leva, F, Nuti, E, Santamaria, S, Pugliesi, I, Morelli, M, Casalini, F, Rossello, A, La Motta, C, Taliani, S, Visse, R, Nagase, H, da Settimo, F, Novellino, E., LA PIETRA, Valeria, Marinelli, Luciana, Cosconati, S., Di Leva, Francesco Saverio, Nuti, E., Santamaria, S., Pugliesi, I., Morelli, M., Casalini, F., Rossello, A., La Motta, C., Taliani, S., Visse, R., Nagase, H., da Settimo, F., and Novellino, Ettore
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Virtual screening ,High selectivity ,Drug Evaluation, Preclinical ,Nanotechnology ,Articular cartilage ,Osteoarthritis ,Matrix Metalloproteinase Inhibitors ,Matrix metalloproteinase ,Crystallography, X-Ray ,Inhibitory Concentration 50 ,User-Computer Interface ,Catalytic Domain ,Matrix Metalloproteinase 13 ,Drug Discovery ,medicine ,Humans ,Protease Inhibitors ,IC50 ,Cancer ,Pharmacology ,MMP ,Chemistry ,Cartilage ,Organic Chemistry ,General Medicine ,medicine.disease ,medicine.anatomical_structure ,Docking (molecular) ,Drug Design ,Molecular docking ,Cancer research ,Osteoarthriti - Abstract
Osteoarthritis (OA) is the leading cause of joint pain and disability in middle-aged and elderly patients, and is characterized by progressive loss of articular cartilage. Among the various matrix metalloproteinases (MMPs), MMP-13 is specifically expressed in the cartilage of human OA patients and is not present in normal adult cartilage. Thus, MMP-13-selective inhibitors are promising candidates in osteoarthritis therapy. Recently, we designed an N-isopropoxy-arylsulfonamide-based hydroxamate inhibitor, which showed low nanomolar activity and high selectivity for MMP-13. In parallel to further studies aiming to assess the in vivo activity of our compound, we screened the Life Chemicals database through computational docking to seek for novel scaffolds as zinc-chelating non-hydroxamate inhibitors. Experimental evaluation of 20 selected candidate compounds verified five novel leads with IC 50 in the low μM range. These newly discovered inhibitors are structurally unrelated to the ones known so far and provide useful scaffolds to develop compounds with more desirable properties. Finally, a first round of structure-based optimization on lead 1 was accomplished and led to an increase in potency of more than 5 fold. © 2011 Elsevier Masson SAS. All rights reserved.
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- 2012
20. Human recombinant beta-secretase immobilized enzyme reactor for fast hits’ selection and characterization from a virtual screening library
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Ettore Novellino, Valeria La Pietra, Luciana Marinelli, Sandro Cosconati, Vincenza Andrisano, Angela De Simone, Francesca Mancini, Angela De Simone, Francesca Mancini, Sandro Cosconati, Luciana Marinelli, Valeria La Pietra, Ettore Novellino, Vincenza Andrisano, De Simone, A., Mancini, F., Cosconati, S., Marinelli, Luciana, LA PIETRA, Valeria, Novellino, Ettore, Andrisano, V., De Simone, A, Mancini, F, Cosconati, Sandro, Marinelli, L, La Pietra, V, and Novellino, E
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Immobilized enzyme ,virtual screening library ,Clinical Biochemistry ,Pharmaceutical Science ,Sensitivity and Specificity ,inhibitor hits screening ,Substrate Specificity ,Analytical Chemistry ,law.invention ,Small Molecule Libraries ,Bioreactors ,law ,LC-Fluorescent detection ,Drug Discovery ,High-Throughput Screening Assays ,Fluorescence Resonance Energy Transfer ,Aspartic Acid Endopeptidases ,Humans ,Inhibition mechanism ,Enzyme Inhibitors ,Mode of action ,Chromatography, High Pressure Liquid ,Spectroscopy ,chemistry.chemical_classification ,Virtual screening ,Chromatography ,Chemistry ,Enzymes, Immobilized ,Combinatorial chemistry ,Fluorescence ,Förster resonance energy transfer ,Enzyme ,Recombinant DNA ,online enzyme activity ,hrBACE1-IMER ,Amyloid Precursor Protein Secretases - Abstract
In the present work, a human recombinant BACE1 immobilized enzyme reactor (hrBACE1-IMER) has been applied for the sensitive fast screening of 38 compounds selected through a virtual screening approach. HrBACE1-IMER was inserted into a liquid chromatograph coupled with a fluorescent detector. A fluorogenic peptide substrate (M-2420), containing the β-secretase site of the Swedish mutation of APP, was injected and cleaved in the on-line HPLC-hrBACE1-IMER system, giving rise to the fluorescent product. The compounds of the library were tested for their ability to inhibit BACE1 in the immobilized format and to reduce the area related to the chromatographic peak of the fluorescent enzymatic product. The results were validated in solution by using two different FRET methods. Due to the efficient virtual screening methodology, more than fifty percent of the selected compounds showed a measurable inhibitory activity. One of the most active compound (a bis-indanone derivative) was characterized in terms of IC50 and Ki determination on the hrBACE1-IMER. Thus, the hrBACE1-IMER has been confirmed as a valid tool for the throughput screening of different chemical entities with potency lower than 30μM for the fast hits' selection and for mode of action determination. © 2012 Elsevier B.V.
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- 2013
21. Progresses in the pursuit of aldose reductase inhibitors: The structure-based lead optimization step
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Vita Maglio, Sara Angiuoli, Ettore Novellino, Federico Da Settimo, Mariateresa Giustiniano, Sandro Cosconati, Stefania Sartini, Salvatore Di Maro, Valeria La Pietra, Luciana Marinelli, Concettina La Motta, Anna Ramunno, Ramunno, A, Cosconati, Sandro, Sartini, S, Maglio, V, Angiuoli, S, La Pietra, V, DI MARO, Salvatore, Giustiniano, M, La Motta, C, Da Settimo, F, Marinelli, L, Novellino, E., Cosconati, S, LA PIETRA, Valeria, Giustiniano, Mariateresa, Marinelli, Luciana, and Novellino, Ettore
- Subjects
Models, Molecular ,medicine.medical_specialty ,Diabetic neuropathy ,Drug Evaluation, Preclinical ,Aldose reductase ,Inflammation ,Pharmacology ,Diabete ,Fidarestat ,Metastasis ,Docking ,Inhibitory Concentration 50 ,Structure-Activity Relationship ,User-Computer Interface ,Aldehyde Reductase ,Diabetes mellitus ,Internal medicine ,Catalytic Domain ,Drug Discovery ,medicine ,Enzyme Inhibitors ,Receptor ,Chemistry ,Organic Chemistry ,General Medicine ,Aldose reductase inhibitors ,medicine.disease ,Endocrinology ,Docking (molecular) ,Enzyme ,medicine.symptom - Abstract
Aldose reductase (ALR2) is a crucial enzyme in the development of the major complications of diabetes mellitus. Very recently it has been demonstrated that the ARL2 inhibitor, fidarestat, significantly prevents inflammatory signals (TNF-α, LPS) that cause cancer (colon, breast, prostate and lung), metastasis, asthma, and other inflammatory diseases. Currently, fidarestat is in phase III clinical trial for diabetic neuropathy and was found to be safe. Thus the finding of novel, potent ARL2 inhibitors is today more than in the past in great demand as they can pave the way for a novel therapeutic approach for a number of diseases besides the diabetes. Herein, starting from the virtual screening-derived ALR2 inhibitor S12728 (1), a rational receptor-based lead optimization has been undertaken. The design and synthetic efforts here reported led to the discovery of several new compounds endowed with low micromolar/submicromolar activities. © 2012 Elsevier Masson SAS. All rights reserved.
- Published
- 2012
22. State-of-the-art methodologies for the discovery and characterization of DNA G-quadruplex binders
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Luigi Petraccone, Francesco Saverio Di Leva, Antonio Randazzo, Bruno Pagano, Roberta Trotta, Valérie Gabelica, Sandro Cosconati, Luciana Marinelli, Stefano De Tito, Valeria La Pietra, Concetta Giancola, Ilaria Lauri, Ettore Novellino, Pagano, B, Cosconati, Sandro, Gabelica, V, Petraccone, L, De Tito, S, Marinelli, L, La Pietra, V, di Leva, F. S., Lauri, I, Trotta, R, Novellino, E, Giancola, C, Randazzo, A., Pagano, Bruno, Cosconati, S., Gabelica, V., Petraccone, Luigi, DE TITO, Stefano, Marinelli, Luciana, LA PIETRA, Valeria, Di Leva, Francesco Saverio, Lauri, Ilaria, Trotta, R., Novellino, Ettore, Giancola, Concetta, and Randazzo, Antonio
- Subjects
Circular dichroism ,Spectrometry, Mass, Electrospray Ionization ,Magnetic Resonance Spectroscopy ,QUADRUPLEX ,TELOMERE ,Computational biology ,Calorimetry ,G-quadruplex ,Ligands ,Fluorescence ,chemistry.chemical_compound ,G-Quadruplex ,Drug Discovery ,Fluorescence Resonance Energy Transfer ,Organic chemistry ,Humans ,DRUG ,Pharmacology ,Chemistry ,Drug discovery ,Circular Dichroism ,Rational design ,Isothermal titration calorimetry ,Nuclear magnetic resonance spectroscopy ,DNA ,Isothermal titration calorimetry (ITC) ,Computational method ,Circular dichroism (CD) ,Mass spectrometry (MS) ,G-Quadruplexes ,Förster resonance energy transfer ,Spectrometry, Fluorescence ,Nuclear magnetic resonance (NMR) - Abstract
Nowadays, the molecular basis of interaction between low molecular weight compounds and biological macromolecules is the subject of numerous investigations aimed at the rational design of molecules with specific therapeutic applications. In the last decades, it has been demonstrated that DNA quadruplexes play a critical role in several biological processes both at telomeric and gene promoting levels thus providing a great stride in the discovery of ligands able to interact with such a biologically relevant DNA conformation. So far, a number of experimental and computational approaches have been successfully employed in order to identify new ligands and to characterize their binding to the DNA. The main focus of this review is the description of these methodologies, placing a particular emphasis on computational methods, isothermal titration calorimetry (ITC), mass spectrometry (MS), nuclear magnetic resonance (NMR), circular dichroism (CD) and fluorescence spectroscopies. © 2012 Bentham Science Publishers.
- Published
- 2011
23. A more detailed picture of the interactions between virtual screening-derived hits and the DNA G-quadruplex: NMR, molecular modelling and ITC studies
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Luigi Martino, Valeria La Pietra, Sandro Cosconati, Stefano De Tito, Maria R. Conte, Ilaria Lauri, Luciano Mayol, Roberta Trotta, Antonio Randazzo, Luciana Marinelli, Ettore Novellino, Trotta, R., De Tito, S., Lauri, Ilaria, LA PIETRA, Valeria, Marinelli, Luciana, Cosconati, S., Martino, L., Conte, M. R., Mayol, Luciano, Novellino, Ettore, Randazzo, Antonio, Trotta, R, De Tito, S, Lauri, I, La Pietra, V, Marinelli, L, Cosconati, Sandro, Martino, L, Conte, Mr, Mayol, L, Novellino, E, Randazzo, A., AAVV, Trotta, Roberta, DE TITO, Stefano, Martino, Luigi, and M. R., Conte
- Subjects
Virtual screening ,Models, Molecular ,NMR titration ,Magnetic Resonance Spectroscopy ,Stereochemistry ,Drug Evaluation, Preclinical ,Calorimetry ,G-quadruplex ,Biochemistry ,chemistry.chemical_compound ,Nmr titration ,Molecule ,heterocyclic compounds ,Binding site ,Binding Sites ,Chemistry ,Distamycins ,Isothermal titration calorimetry ,General Medicine ,Nuclear magnetic resonance spectroscopy ,G-Quadruplexes ,Crystallography ,Brominated G-quadruplex ,DNA - Abstract
The growing amount of literature about G-quadruplex DNA clearly demonstrates that such a structure is no longer viewed as just a biophysical strangeness but it is instead being considered as an important target for the treatment of various human disorders such as cancers or venous thrombosis. In this scenario, with the aim of finding brand new molecular scaffolds able to interact with the groove of the DNA quadruplex [d(TGGGGT)] 4, we recently performed a successful structure-based virtual screening (VS) campaign. As a result, six molecules were found to be somehow groove binders. Herein, we report the results of novel NMR titration experiments of these VS-derived ligands with modified quadruplexes, namely [d(TGG BrGGT)] 4 and [d(TGGGG BrT)] 4. The novel NMR spectroscopy experiments combined with molecular modelling studies, allow for a more detailed picture of the interaction between each binder and the quadruplex DNA. Noteworthy, isothermal titration calorimetry (ITC) measurements on the above-mentioned compounds revealed that 2, 4, and 6 besides their relatively small dimensions bind the DNA quadruplex [d(TGGGGT)] 4 with higher affinity than distamycin A, to the best of our knowledge, the most potent groove binder identified thus far. © 2011 Elsevier Masson SAS. All rights reserved.
- Published
- 2011
24. Editorial: Promising tools in targeted cancer therapy.
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La Pietra V and Montalbano A
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- Humans, Neoplasms drug therapy, Neoplasms pathology, Molecular Targeted Therapy, Antineoplastic Agents pharmacology, Antineoplastic Agents chemistry
- Published
- 2024
- Full Text
- View/download PDF
25. A reverse translational approach reveals the protective roles of Mangifera indica in inflammatory bowel disease.
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Saviano A, Schettino A, Iaccarino N, Mansour AA, Begum J, Marigliano N, Raucci F, Romano F, Riccardi G, Mitidieri E, d'Emmanuele di Villa Bianca R, Bello I, Panza E, Smimmo M, Vellecco V, Rimmer P, Cheesbrough J, Zhi Z, Iqbal TH, Pieretti S, D'Amore VM, Marinelli L, La Pietra V, Sorrentino R, Costa L, Caso F, Scarpa R, Cirino G, Randazzo A, Bucci M, McGettrick HM, Iqbal AJ, and Maione F
- Subjects
- Adult, Humans, Animals, Tumor Necrosis Factor-alpha metabolism, Endothelial Cells metabolism, Intestinal Mucosa, Disease Models, Animal, Mangifera, Inflammatory Bowel Diseases, Colitis
- Abstract
Inflammatory bowel diseases (IBDs) are chronic intestinal disorders often characterized by a dysregulation of T cells, specifically T helper (Th) 1, 17 and T regulatory (Treg) repertoire. Increasing evidence demonstrates that dietary polyphenols from Mangifera indica L. extract (MIE, commonly known as mango) mitigate intestinal inflammation and splenic Th17/Treg ratio. In this study, we aimed to dissect the immunomodulatory and anti-inflammatory properties of MIE using a reverse translational approach, by initially using blood from an adult IBD inception cohort and then investigating the mechanism of action in a preclinical model of T cell-driven colitis. Of clinical relevance, MIE modulates TNF-α and IL-17 levels in LPS spiked sera from IBD patients as an ex vivo model of intestinal barrier breakdown. Preclinically, therapeutic administration of MIE significantly reduced colitis severity, pathogenic T-cell intestinal infiltrate and intestinal pro-inflammatory mediators (IL-6, IL-17A, TNF-α, IL-2, IL-22). Moreover, MIE reversed colitis-induced gut permeability and restored tight junction functionality and intestinal metabolites. Mechanistic insights revealed MIE had direct effects on blood vascular endothelial cells, blocking TNF-α/IFN-γ-induced up-regulation of COX-2 and the DP2 receptors. Collectively, we demonstrate the therapeutic potential of MIE to reverse the immunological perturbance during the onset of colitis and dampen the systemic inflammatory response, paving the way for its clinical use as nutraceutical and/or functional food., (Copyright © 2024 Elsevier Ltd. All rights reserved.)
- Published
- 2024
- Full Text
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26. A combined approach of structure-based virtual screening and NMR to interrupt the PD-1/PD-L1 axis: Biphenyl-benzimidazole containing compounds as novel PD-L1 inhibitors.
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Donati G, Viviano M, D'Amore VM, Cipriano A, Diakogiannaki I, Amato J, Tomassi S, Brancaccio D, Russomanno P, Di Leva FS, Arosio D, Seneci P, Taliani S, Magiera-Mularz K, Musielak B, Skalniak L, Holak TA, Castellano S, La Pietra V, and Marinelli L
- Subjects
- B7-H1 Antigen, Ligands, Structure-Activity Relationship, Benzimidazoles pharmacology, Water, Immune Checkpoint Inhibitors, Programmed Cell Death 1 Receptor, Biphenyl Compounds
- Abstract
Immunotherapy has emerged as a game-changing approach for cancer treatment. Although monoclonal antibodies (mAbs) targeting the programmed cell death protein 1/programmed cell death protein 1 ligand 1 (PD-1/PD-L1) axis have entered the market revolutionizing the treatment landscape of many cancer types, small molecules, although presenting several advantages including the possibility of oral administration and/or reduced costs, struggled to enter in clinical trials, suffering of water insolubility and/or inadequate potency compared with mAbs. Thus, the search for novel scaffolds for both the design of effective small molecules and possible synergistic strategies is an ongoing field of interest. In an attempt to find novel chemotypes, a virtual screening approach was employed, resulting in the identification of new chemical entities with a certain binding capability, the most versatile of which was the benzimidazole-containing compound 10. Through rational design, a small library of its derivatives was synthesized and evaluated. The homogeneous time-resolved fluorescence (HTRF) assay revealed that compound 17 shows the most potent inhibitory activity (IC
50 ) in the submicromolar range and notably, differently from the major part of PD-L1 inhibitors, exhibits satisfactory water solubility properties. These findings highlight the potential of benzimidazole-based compounds as novel promising candidates for PD-L1 inhibition., (© 2023 The Authors. Archiv der Pharmazie published by Wiley-VCH GmbH on behalf of Deutsche Pharmazeutische Gesellschaft.)- Published
- 2024
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27. Development and Nanoparticle-Mediated Delivery of Novel MDM2/MDM4 Heterodimer Peptide Inhibitors to Enhance 5-Fluorouracil Nucleolar Stress in Colorectal Cancer Cells.
- Author
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Merlino F, Pecoraro A, Longobardi G, Donati G, Di Leva FS, Brignola C, Piccarducci R, Daniele S, Martini C, Marinelli L, Russo G, Quaglia F, Conte C, Russo A, and La Pietra V
- Subjects
- Humans, Fluorouracil pharmacology, Tumor Suppressor Protein p53 metabolism, Apoptosis, Peptides pharmacology, Cell Line, Tumor, Proto-Oncogene Proteins c-mdm2 metabolism, Proto-Oncogene Proteins metabolism, Cell Cycle Proteins metabolism, Antineoplastic Agents pharmacology, Antineoplastic Agents therapeutic use, Colorectal Neoplasms drug therapy, Nanoparticles
- Abstract
Colorectal cancer (CRC) often involves wild-type p53 inactivation by MDM2 and MDM4 overexpression, promoting tumor progression and resistance to 5-fluoruracil (5-FU). Disrupting the MDM2/4 heterodimer can proficiently reactivate p53, sensitizing cancer cells to 5-FU. Herein, we developed 16 peptides based on Pep3 ( 1 ), the only known peptide acting through this mechanism. The new peptides, notably 3 and 9 , showed lower IC
50 values than 1 . When incorporated into tumor-targeted biodegradable nanoparticles, these exhibited cytotoxicity against three different CRC cell lines. Notably, NPs/ 9 caused a significant increase in p53 levels associated with a strong increment of its main downstream target p21 inducing apoptosis. Also, the combined treatment of 9 with 5-FU caused the activation of nucleolar stress and a synergic apoptotic effect. Hence, the co-delivery of MDM2/4 heterodimer disruptors with 5-FU through nanoparticles might be a promising strategy to overcome drug resistance in CRC.- Published
- 2024
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28. Theoretical and experimental studies on the interaction of biphenyl ligands with human and murine PD-L1: Up-to-date clues for drug design.
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Donati G, D'Amore VM, Russomanno P, Cerofolini L, Amato J, Marzano S, Salobehaj M, Rizzo D, Assoni G, Carotenuto A, La Pietra V, Arosio D, Seneci P, Fragai M, Brancaccio D, Di Leva FS, and Marinelli L
- Abstract
Today it is widely recognized that the PD-1/PD-L1 axis plays a fundamental role in escaping the immune system in cancers, so that anti-PD-1/PD-L1 antibodies have been evaluated for their antitumor properties in more than 1000 clinical trials. As a result, some of them have entered the market revolutionizing the treatment landscape of specific cancer types. Nonetheless, a new era based on the development of small molecules as anti PD-L1 drugs has begun. There are, however, some limitations to advancing these compounds into clinical stages including the possible difficulty in counteracting the PD-1/PD-L1 interaction in vivo, the discrepancy between the in vitro IC
50 (HTFR assay) and cellular EC50 (immune checkpoint blockade co-culture assay), and the differences in ligands' affinity between human and murine PD-L1, which can affect their preclinical evaluation. Here, an extensive theoretical study, assisted by MicroScale Thermophoresis binding assays and NMR experiments, was performed to provide an atomistic picture of the binding event of three representative biphenyl-based compounds in both human and murine PD-L1. Structural determinants of the species' specificity were unraveled, providing unprecedented details useful for the design of next generation anti-PD-L1 molecules., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2023 Published by Elsevier B.V. on behalf of Research Network of Computational and Structural Biotechnology.)- Published
- 2023
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29. HuR modulation counteracts lipopolysaccharide response in murine macrophages.
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Bonomo I, Assoni G, La Pietra V, Canarutto G, Facen E, Donati G, Zucal C, Genovese S, Micaelli M, Pérez-Ràfols A, Robbiati S, Kontoyannis DL, De Matteo M, Fragai M, Seneci P, Marinelli L, Arosio D, Piazza S, and Provenzani A
- Subjects
- Mice, Animals, Macrophages metabolism, RNA metabolism, RNA, Messenger genetics, Lipopolysaccharides pharmacology, Lipopolysaccharides metabolism, ELAV-Like Protein 1 genetics, ELAV-Like Protein 1 metabolism
- Abstract
Lipopolysaccharide (LPS) exposure to macrophages induces an inflammatory response, which is regulated at the transcriptional and post-transcriptional levels. HuR (ELAVL1) is an RNA-binding protein that regulates cytokines and chemokines transcripts containing AU/U-rich elements (AREs) and mediates the LPS-induced response. Here, we show that small-molecule tanshinone mimics (TMs) inhibiting HuR-RNA interaction counteract LPS stimulus in macrophages. TMs exist in solution in keto-enolic tautomerism, and molecular dynamic calculations showed the ortho-quinone form inhibiting binding of HuR to mRNA targets. TM activity was lost in vitro by blocking the diphenolic reduced form as a diacetate, but resulted in prodrug-like activity in vivo. RNA and ribonucleoprotein immunoprecipitation sequencing revealed that LPS induces a strong coupling between differentially expressed genes and HuR-bound genes, and TMs reduced such interactions. TMs decreased the association of HuR with genes involved in chemotaxis and immune response, including Cxcl10, Il1b and Cd40, reducing their expression and protein secretion in primary murine bone marrow-derived macrophages and in an LPS-induced peritonitis model. Overall, TMs show anti-inflammatory properties in vivo and suggest HuR as a potential therapeutic target for inflammation-related diseases., Competing Interests: Competing interests The authors declare no competing or financial interests., (© 2023. Published by The Company of Biologists Ltd.)
- Published
- 2023
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30. Identification of a Novel p53 Modulator Endowed with Antitumoural and Antibacterial Activity through a Scaffold Repurposing Approach.
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Nuti E, La Pietra V, Daniele S, Cuffaro D, Ciccone L, Giacomelli C, Cason C, Carotenuto A, D'Amore VM, Pozzo ED, Costa B, Di Leo R, Comar M, Marinelli L, Martini C, and Rossello A
- Abstract
Intracellular pathogens, such as Chlamydia trachomatis , have been recently shown to induce degradation of p53 during infection, thus impairing the protective response of the host cells. Therefore, p53 reactivation by disruption of the p53-MDM2 complex could reduce infection and restore pro-apoptotic effect of p53. Here, we report the identification of a novel MDM2 inhibitor with potential antitumoural and antibacterial activity able to reactivate p53. A virtual screening was performed on an in-house chemical library, previously synthesised for other targets, and led to the identification of a hit compound with a benzo[a]dihydrocarbazole structure, RM37. This compound induced p53 up-regulation in U343MG glioblastoma cells by blocking MDM2-p53 interaction and reduced tumour cell growth. NMR studies confirmed its ability to dissociate the MDM2-p53 complex. Notably, RM37 reduced Chlamydia infection in HeLa cells in a concentration-dependent manner and ameliorated the inflammatory status associated with infection.
- Published
- 2022
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31. HuR-targeted agents: An insight into medicinal chemistry, biophysical, computational studies and pharmacological effects on cancer models.
- Author
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Assoni G, La Pietra V, Digilio R, Ciani C, Licata NV, Micaelli M, Facen E, Tomaszewska W, Cerofolini L, Pérez-Ràfols A, Varela Rey M, Fragai M, Woodhoo A, Marinelli L, Arosio D, Bonomo I, Provenzani A, and Seneci P
- Subjects
- Animals, Drug Delivery Systems methods, Gene Silencing, Humans, Inflammation Mediators metabolism, Molecular Weight, Neoplasms drug therapy, RNA, Messenger pharmacology, RNA, Small Interfering pharmacology, ELAV-Like Protein 1 antagonists & inhibitors, ELAV-Like Protein 1 metabolism, Neoplasms physiopathology, RNA metabolism, RNA pharmacology
- Abstract
The Human antigen R (HuR) protein is an RNA-binding protein, ubiquitously expressed in human tissues, that orchestrates target RNA maturation and processing both in the nucleus and in the cytoplasm. A survey of known modulators of the RNA-HuR interactions is followed by a description of its structure and molecular mechanism of action - RRM domains, interactions with RNA, dimerization, binding modes with naturally occurring and synthetic HuR inhibitors. Then, the review focuses on HuR as a validated molecular target in oncology and briefly describes its role in inflammation. Namely, we show ample evidence for the involvement of HuR in the hallmarks and enabling characteristics of cancer, reporting findings from in vitro and in vivo studies; and we provide abundant experimental proofs of a beneficial role for the inhibition of HuR-mRNA interactions through silencing (CRISPR, siRNA) or pharmacological inhibition (small molecule HuR inhibitors)., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier B.V. All rights reserved.)
- Published
- 2022
- Full Text
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32. Enriching the Arsenal of Pharmacological Tools against MICAL2.
- Author
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Barravecchia I, Barresi E, Russo C, Scebba F, De Cesari C, Mignucci V, De Luca D, Salerno S, La Pietra V, Giustiniano M, Pelliccia S, Brancaccio D, Donati G, Da Settimo F, Taliani S, Angeloni D, and Marinelli L
- Subjects
- Humans, Molecular Structure, Anilides chemistry, Anilides pharmacology, Benzamides chemistry, Benzamides pharmacology, Enzyme Inhibitors chemistry, Enzyme Inhibitors pharmacology, Microfilament Proteins antagonists & inhibitors, Microfilament Proteins metabolism, Oxidoreductases antagonists & inhibitors, Oxidoreductases metabolism, Small Molecule Libraries chemistry, Small Molecule Libraries pharmacology
- Abstract
Molecule interacting with CasL 2 (MICAL2), a cytoskeleton dynamics regulator, are strongly expressed in several human cancer types, especially at the invasive front, in metastasizing cancer cells and in the neo-angiogenic vasculature. Although a plethora of data exist and stress a growing relevance of MICAL2 to human cancer, it is worth noting that only one small-molecule inhibitor, named CCG-1423 (1), is known to date. Herein, with the aim to develop novel MICAL2 inhibitors, starting from CCG-1423 (1), a small library of new compounds was synthetized and biologically evaluated on human dermal microvascular endothelial cells (HMEC-1) and on renal cell adenocarcinoma (786-O) cells. Among the novel compounds, 10 and 7 gave interesting results in terms of reduction in cell proliferation and/or motility, whereas no effects were observed in MICAL2-knocked down cells. Aside from the interesting biological activities, this work provides the first structure-activity relationships (SARs) of CCG-1423 (1), thus providing precious information for the discovery of new MICAL2 inhibitors.
- Published
- 2021
- Full Text
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33. Interfering with the Tumor-Immune Interface: Making Way for Triazine-Based Small Molecules as Novel PD-L1 Inhibitors.
- Author
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Russomanno P, Assoni G, Amato J, D'Amore VM, Scaglia R, Brancaccio D, Pedrini M, Polcaro G, La Pietra V, Orlando P, Falzoni M, Cerofolini L, Giuntini S, Fragai M, Pagano B, Donati G, Novellino E, Quintavalle C, Condorelli G, Sabbatino F, Seneci P, Arosio D, Pepe S, and Marinelli L
- Subjects
- Calorimetry, Differential Scanning, Cell Line, Tumor, Coculture Techniques, Humans, Immune Checkpoint Inhibitors chemistry, Models, Molecular, Small Molecule Libraries chemistry, Structure-Activity Relationship, Triazines chemistry, B7-H1 Antigen antagonists & inhibitors, Immune Checkpoint Inhibitors pharmacology, Neoplasms immunology, Neoplasms pathology, Small Molecule Libraries pharmacology, Triazines pharmacology
- Abstract
The inhibition of the PD-1/PD-L1 axis by monoclonal antibodies has achieved remarkable success in treating a growing number of cancers. However, a novel class of small organic molecules, with BMS-202 ( 1 ) as the lead, is emerging as direct PD-L1 inhibitors. Herein, we report a series of 2,4,6-tri- and 2,4-disubstituted 1,3,5-triazines, which were synthesized and assayed for their PD-L1 binding by NMR and homogeneous time-resolved fluorescence. Among them, compound 10 demonstrated to strongly bind with the PD-L1 protein and challenged it in a co-culture of PD-L1 expressing cancer cells (PC9 and HCC827 cells) and peripheral blood mononuclear cells enhanced antitumor immune activity of the latter. Compound 10 significantly increased interferon γ release and apoptotic induction of cancer cells, with low cytotoxicity in healthy cells when compared to 1 , thus paving the way for subsequent preclinical optimization and medical applications.
- Published
- 2021
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34. CXCR4 antagonism sensitizes cancer cells to novel indole-based MDM2/4 inhibitors in glioblastoma multiforme.
- Author
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Daniele S, La Pietra V, Piccarducci R, Pietrobono D, Cavallini C, D'Amore VM, Cerofolini L, Giuntini S, Russomanno P, Puxeddu M, Nalli M, Pedrini M, Fragai M, Luchinat C, Novellino E, Taliani S, La Regina G, Silvestri R, Martini C, and Marinelli L
- Subjects
- Brain Neoplasms enzymology, Brain Neoplasms genetics, Brain Neoplasms pathology, Cell Cycle Proteins metabolism, Cell Line, Tumor, Cell Movement drug effects, Cell Proliferation drug effects, Drug Synergism, Glioblastoma enzymology, Glioblastoma genetics, Glioblastoma pathology, Humans, Neoplasm Invasiveness, Neoplastic Stem Cells drug effects, Neoplastic Stem Cells enzymology, Neoplastic Stem Cells pathology, Neurogenesis drug effects, Proto-Oncogene Proteins metabolism, Proto-Oncogene Proteins c-mdm2 metabolism, Receptors, CXCR4 metabolism, Signal Transduction, Spheroids, Cellular, Tumor Suppressor Protein p53 genetics, Tumor Suppressor Protein p53 metabolism, Antineoplastic Combined Chemotherapy Protocols pharmacology, Benzylamines pharmacology, Brain Neoplasms drug therapy, Cell Cycle Proteins antagonists & inhibitors, Cyclams pharmacology, Glioblastoma drug therapy, Indoles pharmacology, Proto-Oncogene Proteins antagonists & inhibitors, Proto-Oncogene Proteins c-mdm2 antagonists & inhibitors, Receptors, CXCR4 antagonists & inhibitors
- Abstract
Glioblastoma Multiforme (GBM) is a highly invasive primary brain tumour characterized by chemo- and radio-resistance and poor overall survival. GBM can present an aberrant functionality of p53, caused by the overexpression of the murine double minute 2 protein (MDM2) and its analogue MDM4, which may influence the response to conventional therapies. Moreover, tumour resistance/invasiveness has been recently attributed to an overexpression of the chemokine receptor CXCR4, identified as a pivotal mediator of glioma neovascularization. Notably, CXCR4 and MDM2-4 cooperate in promoting tumour invasion and progression. Although CXCR4 actively promotes MDM2 activation leading to p53 inactivation, MDM2-4 knockdown induces the downregulation of CXCR4 gene transcription. Our study aimed to assess if the CXCR4 signal blockade could enhance glioma cells' sensitivity to the inhibition of the p53-MDMs axis. Rationally designed inhibitors of MDM2/4 were combined with the CXCR4 antagonist, AMD3100, in human GBM cells and GBM stem-like cells (neurospheres), which are crucial for tumour recurrence and chemotherapy resistance. The dual MDM2/4 inhibitor RS3594 and the CXCR4 antagonist AMD3100 reduced GBM cell invasiveness and migration in single-agent treatment and mainly in combination. AMD3100 sensitized GBM cells to the antiproliferative activity of RS3594. It is noteworthy that these two compounds present synergic effects on cancer stem components: RS3594 inhibited the growth and formation of neurospheres, AMD3100 induced differentiation of neurospheres while enhancing RS3594 effectiveness preventing their proliferation/clonogenicity. These results confirm that blocking CXCR4/MDM2/4 represents a valuable strategy to reduce GBM proliferation and invasiveness, acting on the stem cell component too., (Copyright © 2021 Elsevier B.V. All rights reserved.)
- Published
- 2021
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35. Design, synthesis and biological evaluation of novel TRβ selective agonists sustained by ADME-toxicity analysis.
- Author
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Runfola M, Sestito S, Bellusci L, La Pietra V, D'Amore VM, Kowalik MA, Chiellini G, Gul S, Perra A, Columbano A, Marinelli L, Novellino E, and Rapposelli S
- Subjects
- Animals, Dose-Response Relationship, Drug, Hep G2 Cells, Humans, Male, Molecular Structure, Pyridazines chemical synthesis, Pyridazines chemistry, Rats, Rats, Inbred F344, Structure-Activity Relationship, Uracil chemical synthesis, Uracil chemistry, Uracil pharmacology, Drug Design, Pyridazines pharmacology, Thyroid Hormone Receptors beta agonists, Uracil analogs & derivatives
- Abstract
Although triiodothyronine (T3) induces several beneficial effects on lipid metabolism, its use is hampered by toxic side-effects, such as tachycardia, arrhythmia, heart failure, bone and muscle catabolism and mood disturbances. Since the α isoform of thyroid hormone receptors (TRs) is the main cause of T3-related harmful effects, several efforts have been made to develop selective agonists of the β isoform that could induce some beneficial effects (i.e. lowering triglyceride and cholesterol levels reducing obesity and improving metabolic syndrome), while overcoming most of the adverse T3-dependent side effects. Herein, we describe the drug discovery process sustained by ADME-Toxicity analysis that led us to identify novel agonists with selectivity for the isoform TRβ and an acceptable off-target and absorption, distribution metabolism, excretion and toxicity (ADME-Tox) profile. Within the small series of compounds synthesized, derivatives 1 and 3, emerge from this analysis as "potentially safe" to be engaged in preclinical studies. In in vitro investigation proved that both compounds were able to reduce lipid accumulation in HepG2 and promote lipolysis with comparable effects to those elicited by T3, used as reference drug. Moreover, a preliminary in vivo study confirmed the apparent lack of toxicity, thus suggesting compounds 1 and 3 as new potential TRβ-selective thyromimetics., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2019 Elsevier Masson SAS. All rights reserved.)
- Published
- 2020
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36. Correction to "Discovery of the First-in-Class GSK-3β/HDAC Dual Inhibitor as Disease-Modifying Agent To Combat Alzheimer's Disease".
- Author
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De Simone A, La Pietra V, Betari N, Petragnani N, Conte M, Daniele S, Pietrobono D, Martini C, Petralla S, Casadei R, Davani L, Frabetti F, Russomanno P, Novellino E, Montanari S, Tumiatti V, Ballerini P, Sarno F, Nebbioso A, Altucci L, Monti B, Andrisano V, and Milelli A
- Abstract
[This corrects the article DOI: 10.1021/acsmedchemlett.8b00507.].
- Published
- 2019
- Full Text
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37. Long lasting inhibition of Mdm2-p53 interaction potentiates mesenchymal stem cell differentiation into osteoblasts.
- Author
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Daniele S, Giacomelli C, Pietrobono D, Barresi E, Piccarducci R, La Pietra V, Taliani S, Da Settimo F, Marinelli L, Novellino E, Martini C, and Trincavelli ML
- Subjects
- Cells, Cultured, Cyclic AMP Response Element-Binding Protein metabolism, Extracellular Signal-Regulated MAP Kinases metabolism, G-Protein-Coupled Receptor Kinase 2 metabolism, Humans, MAP Kinase Signaling System drug effects, Mesenchymal Stem Cells cytology, Osteoblasts cytology, Protein Binding drug effects, Proto-Oncogene Proteins c-mdm2 antagonists & inhibitors, Receptor, Adenosine A2B metabolism, Cell Differentiation drug effects, Dipeptides pharmacology, Indoles pharmacology, Mesenchymal Stem Cells metabolism, Osteoblasts metabolism, Proto-Oncogene Proteins c-mdm2 metabolism, Tumor Suppressor Protein p53 metabolism
- Abstract
The osteoblast generation from Mesenchymal stem cells (MSCs) is tightly coordinated by transcriptional networks and signalling pathways that control gene expression and protein stability of osteogenic "master transcription factors". Among these pathways, a great attention has been focused on p53 and its physiological negative regulator, the E3 ligase Murine double minute 2 (Mdm2). Nevertheless, the signalling that regulates Mdm2-p53 axis in osteoblasts remain to be elucidated, also considering that Mdm2 possesses numerous p53-independent activities and interacts with additional proteins. Herein, the effects of Mdm2 modulation on MSC differentiation were examined by the use of short- and long-lasting inhibitors of the Mdm2-p53 complex. The long-lasting Mdm2-p53 dissociation was demonstrated to enhance the MSC differentiation into osteoblasts. The increase of Mdm2 levels promoted its association to G protein-coupled receptors kinase (GRK) 2, one of the most relevant kinases involved in the desensitization of G protein-coupled receptors (GPCRs). In turn, the long-lasting Mdm2-p53 dissociation decreased GRK2 levels and favoured the functionality of A
2B Adenosine Receptors (A2B ARs), a GPCR dictating MSC fate. EB148 facilitated cAMP accumulation, and mediated a sustained activation of extracellular signal-regulated kinases (ERKs) and cAMP response element-binding protein (CREB). Such pro-osteogenic effects were not detectable by using the reversible Mdm2-p53 complex inhibitor, suggesting the time course of Mdm2-p53 dissociation may impact on intracellular proteins involved in cell differentiation fate. These results suggest that the long-lasting Mdm2 binding plays a key role in the mobilization of intracellular proteins that regulate the final biological outcome of MSCs., (Copyright © 2019 Elsevier B.V. All rights reserved.)- Published
- 2019
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38. Benzothiopyranoindole- and pyridothiopyranoindole-based antiproliferative agents targeting topoisomerases.
- Author
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Salerno S, La Pietra V, Hyeraci M, Taliani S, Robello M, Barresi E, Milite C, Simorini F, García-Argáez AN, Marinelli L, Novellino E, Da Settimo F, Marini AM, and Dalla Via L
- Subjects
- Antineoplastic Agents chemistry, Antineoplastic Agents pharmacology, Apoptosis drug effects, Cell Line, Tumor, Cell Proliferation drug effects, DNA metabolism, Humans, Indoles chemical synthesis, Indoles chemistry, Indoles metabolism, Molecular Docking Simulation, Structure-Activity Relationship, Topoisomerase I Inhibitors chemical synthesis, Topoisomerase II Inhibitors chemical synthesis, Antineoplastic Agents chemical synthesis, Indoles pharmacology, Topoisomerase I Inhibitors chemistry, Topoisomerase II Inhibitors chemistry
- Abstract
New benzothiopyranoindoles (5a-l) and pyridothiopyranoindoles (5m-t), featuring different combinations of substituents (H, Cl, OCH
3 ) at R2 -R4 positions and protonatable R1 -dialkylaminoalkyl chains, were synthesized and biologically assayed on three human tumor cell lines, showing significant antiproliferative activity (GI50 values spanning from 0.31 to 6.93 μM) and pro-apoptotic effect. Linear flow dichroism experiments indicate the ability of both chromophores to form a molecular complex with DNA, following an intercalative mode of binding. All compounds displayed a moderate ability to inhibit the relaxation activity of both topoisomerases I and II, reasonably correlated to their intercalative capacities. Cleavable assay performed with topoisomerase I revealed a significant poisoning effect for compounds 5g, 5h, 5s, and 5t. A theoretical model provided by hydrated docking calculations clarified the role of the R1 -R4 substituents on the topoisomerase I poison activity, revealing a crucial role of the R2 -OCH3 group., (Copyright © 2019 Elsevier Masson SAS. All rights reserved.)- Published
- 2019
- Full Text
- View/download PDF
39. Discovery of the First-in-Class GSK-3β/HDAC Dual Inhibitor as Disease-Modifying Agent To Combat Alzheimer's Disease.
- Author
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De Simone A, La Pietra V, Betari N, Petragnani N, Conte M, Daniele S, Pietrobono D, Martini C, Petralla S, Casadei R, Davani L, Frabetti F, Russomanno P, Novellino E, Montanari S, Tumiatti V, Ballerini P, Sarno F, Nebbioso A, Altucci L, Monti B, Andrisano V, and Milelli A
- Abstract
Several evidence pointed out the role of epigenetics in Alzheimer's disease (AD) revealing strictly relationships between epigenetic and "classical" AD targets. Based on the reported connection among histone deacetylases (HDACs) and glycogen synthase kinase 3β (GSK-3β), herein we present the discovery and the biochemical characterization of the first-in-class hit compound able to exert promising anti-AD effects by modulating the targeted proteins in the low micromolar range of concentration. Compound 11 induces an increase in histone acetylation and a reduction of tau phosphorylation. It is nontoxic and protective against H
2 O2 and 6-OHDA stimuli in SH-SY5Y and in CGN cell lines, respectively. Moreover, it promotes neurogenesis and displays immunomodulatory effects. Compound 11 shows no lethality in a wt-zebrafish model (<100 μM) and high water solubility., Competing Interests: The authors declare no competing financial interest.- Published
- 2019
- Full Text
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40. Simultaneous Targeting of RGD-Integrins and Dual Murine Double Minute Proteins in Glioblastoma Multiforme.
- Author
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Merlino F, Daniele S, La Pietra V, Di Maro S, Di Leva FS, Brancaccio D, Tomassi S, Giuntini S, Cerofolini L, Fragai M, Luchinat C, Reichart F, Cavallini C, Costa B, Piccarducci R, Taliani S, Da Settimo F, Martini C, Kessler H, Novellino E, and Marinelli L
- Subjects
- Animals, Cell Line, Tumor, Integrin alpha5beta1 antagonists & inhibitors, Integrin alphaVbeta3 antagonists & inhibitors, Mice, Models, Molecular, Peptidomimetics pharmacology, Protein Conformation, Proto-Oncogene Proteins c-mdm2 chemistry, Glioblastoma drug therapy, Glioblastoma metabolism, Integrin alpha5beta1 metabolism, Integrin alphaVbeta3 metabolism, Molecular Targeted Therapy methods, Oligopeptides chemistry, Proto-Oncogene Proteins c-mdm2 metabolism
- Abstract
In the fight against Glioblastoma Multiforme, recent literature data have highlighted that integrin α5β1 and p53 are part of convergent pathways in the control of glioma apoptosis. This observation prompted us to seek a molecule able to simultaneously modulate both target families. Analyzing the results of a previous virtual screening against murine double minute 2 protein (MDM2), we envisaged that Arg-Gly-Asp (RGD)-mimetic molecules could be inhibitors of MDM2/4. Herein, we present the discovery of compound 7, which inhibits both MDM2/4 and α5β1/αvβ3 integrins. A lead optimization campaign was carried out on 7 with the aim to preserve the activities on integrins while improving those on MDM proteins. Compound 9 turned out to be a potent MDM2/4 and α5β1/αvβ3 blocker. In p53-wild type glioma cells, 9 arrested cell cycle and proliferation and strongly reduced cell invasiveness, emerging as the first molecule of a novel class of integrin/MDM inhibitors, which might be especially useful in subpopulations of patients with glioblastoma expressing a functional p53 concomitantly with a high level of α5β1 integrin.
- Published
- 2018
- Full Text
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41. Challenging clinically unresponsive medullary thyroid cancer: Discovery and pharmacological activity of novel RET inhibitors.
- Author
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La Pietra V, Sartini S, Botta L, Antonelli A, Ferrari SM, Fallahi P, Moriconi A, Coviello V, Quattrini L, Ke YY, Hsing-Pang H, Da Settimo F, Novellino E, La Motta C, and Marinelli L
- Subjects
- Antineoplastic Agents chemical synthesis, Antineoplastic Agents chemistry, Carcinoma, Neuroendocrine metabolism, Cell Line, Tumor, Cell Proliferation drug effects, Dose-Response Relationship, Drug, Drug Screening Assays, Antitumor, Humans, Molecular Structure, Protein Kinase Inhibitors chemical synthesis, Protein Kinase Inhibitors chemistry, Proto-Oncogene Proteins c-ret genetics, Proto-Oncogene Proteins c-ret metabolism, Structure-Activity Relationship, Thyroid Gland metabolism, Thyroid Gland pathology, Thyroid Neoplasms metabolism, Antineoplastic Agents pharmacology, Carcinoma, Neuroendocrine drug therapy, Drug Discovery, Protein Kinase Inhibitors pharmacology, Proto-Oncogene Proteins c-ret antagonists & inhibitors, Thyroid Gland drug effects, Thyroid Neoplasms drug therapy
- Abstract
It is now known that "gain of function" mutations of RET (REarranged during Transfection) kinase are specific and key oncogenic events in the onset of thyroid gland cancers such as the Medullary Thyroid Carcinoma (MTC). Although a number of RET inhibitors exist and are capable of inhibiting RET variants, in which mutations are outside the enzyme active site, the majority becomes dramatically ineffective when mutations are within the protein active site (V804L and V804M). Pursuing a receptor-based virtual screening against the kinase domain of RET, we found that compound 5 is able to inhibit efficiently both wild type and V804L mutant RET. Compound 5 was able to significantly reduce proliferation of both commercially available TT cell lines and surgical thyroid tissues obtained from patients with MTC and displayed a suitable drug-like profile, thus standing out as a promising candidate for further development towards the treatment of clinically unresponsive MTC., (Copyright © 2018 Elsevier Masson SAS. All rights reserved.)
- Published
- 2018
- Full Text
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42. Bax Activation Blocks Self-Renewal and Induces Apoptosis of Human Glioblastoma Stem Cells.
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Daniele S, Pietrobono D, Costa B, Giustiniano M, La Pietra V, Giacomelli C, La Regina G, Silvestri R, Taliani S, Trincavelli ML, Da Settimo F, Novellino E, Martini C, and Marinelli L
- Subjects
- Apoptosis drug effects, Apoptosis physiology, Caspase 3 metabolism, Caspase 7 metabolism, Cell Cycle drug effects, Cell Cycle physiology, Cell Line, Tumor, Cell Proliferation drug effects, Cell Proliferation physiology, Cell Survival drug effects, Cell Survival physiology, Central Nervous System Neoplasms metabolism, Central Nervous System Neoplasms pathology, Dacarbazine analogs & derivatives, Dacarbazine pharmacology, Drug Therapy, Combination, Glioblastoma metabolism, Glioblastoma pathology, Humans, Hydrazones pharmacology, Membrane Potential, Mitochondrial drug effects, Neoplastic Stem Cells metabolism, Neoplastic Stem Cells pathology, Pyrazoles pharmacology, Temozolomide, Antineoplastic Agents pharmacology, Central Nervous System Neoplasms drug therapy, Glioblastoma drug therapy, Neoplastic Stem Cells drug effects, bcl-2-Associated X Protein metabolism
- Abstract
Glioblastoma (GBM) is characterized by a poor response to conventional chemotherapeutic agents, attributed to the insurgence of drug resistance mechanisms and to the presence of a subpopulation of glioma stem cells (GSCs). GBM cells and GSCs present, among others, an overexpression of antiapoptotic proteins and an inhibition of pro-apoptotic ones, which help to escape apoptosis. Among pro-apoptotic inducers, the Bcl-2 family protein Bax has recently emerged as a promising new target in cancer therapy along with first BAX activators (BAM7, Compound 106, and SMBA1). Herein, a derivative of BAM-7, named BTC-8, was employed to explore the effects of Bax activation in different human GBM cells and in their stem cell subpopulation. BTC-8 inhibited GBM cell proliferation, arrested the cell cycle, and induced apoptosis through the induction of mitochondrial membrane permeabilization. Most importantly, BTC-8 blocked proliferation and self-renewal of GSCs and induced their apoptosis. Notably, BTC-8 was demonstrated to sensitize both GBM cells and GSCs to the alkylating agent Temozolomide. Overall, our findings shed light on the effects and the relative molecular mechanisms related to Bax activation in GBM, and they suggest Bax-targeting compounds as promising therapeutic tools against the GSC reservoir.
- Published
- 2018
- Full Text
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43. Computer-Aided Identification and Lead Optimization of Dual Murine Double Minute 2 and 4 Binders: Structure-Activity Relationship Studies and Pharmacological Activity.
- Author
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Giustiniano M, Daniele S, Pelliccia S, La Pietra V, Pietrobono D, Brancaccio D, Cosconati S, Messere A, Giuntini S, Cerofolini L, Fragai M, Luchinat C, Taliani S, La Regina G, Da Settimo F, Silvestri R, Martini C, Novellino E, and Marinelli L
- Subjects
- Apoptosis drug effects, Cell Line, Tumor, Cell Proliferation drug effects, Computer-Aided Design, Drug Design, Genes, p53, High-Throughput Screening Assays, Humans, Magnetic Resonance Spectroscopy, Models, Molecular, Neoplastic Stem Cells, Proto-Oncogene Proteins drug effects, Proto-Oncogene Proteins c-mdm2 drug effects, Structure-Activity Relationship, Antineoplastic Agents chemical synthesis, Antineoplastic Agents pharmacology, Proto-Oncogene Proteins metabolism, Proto-Oncogene Proteins c-mdm2 metabolism
- Abstract
The function of p53 protein, also known as "genome guardian", might be impaired by the overexpression of its primary cellular inhibitor, the murine double minute 2 protein (MDM2). However, the recent finding that MDM2-selective inhibitors induce high levels of its homologue MDM4, prompt us to identify, through a receptor-based virtual screening on an in house database, dual MDM2/MDM4 binders. Compound 1 turned out to possess an IC
50 of 93.7 and of 4.6 nM on MDM2 and MDM4, respectively. A series of compounds were synthesized to optimize its activity on MDM2. As a result, compound 12 showed low nanomolar IC50 for both targets. NMR studies confirmed the pocket of binding of 12 as predicted by the Glide docking software. Notably, 12 was able to cause concentration-dependent inhibition of cell proliferation, yielding an IC50 value of 356 ± 21 nM in neuroblastoma SHSY5Y cells and proved even to efficiently block cancer stem cell growth.- Published
- 2017
- Full Text
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44. Exploring the N-Terminal Region of C-X-C Motif Chemokine 12 (CXCL12): Identification of Plasma-Stable Cyclic Peptides As Novel, Potent C-X-C Chemokine Receptor Type 4 (CXCR4) Antagonists.
- Author
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Di Maro S, Trotta AM, Brancaccio D, Di Leva FS, La Pietra V, Ieranò C, Napolitano M, Portella L, D'Alterio C, Siciliano RA, Sementa D, Tomassi S, Carotenuto A, Novellino E, Scala S, and Marinelli L
- Subjects
- Amino Acid Sequence, Cell Line, Tumor, Cell Movement drug effects, Colonic Neoplasms drug therapy, Humans, Leukemia drug therapy, Models, Molecular, Phosphorylation drug effects, Antineoplastic Agents chemistry, Antineoplastic Agents pharmacology, Chemokine CXCL12 chemistry, Chemokine CXCL12 pharmacology, Peptides, Cyclic chemistry, Peptides, Cyclic pharmacology, Receptors, CXCR4 antagonists & inhibitors
- Abstract
We previously reported the discovery of a CXCL12-mimetic cyclic peptide (2) as a selective CXCR4 antagonist showing promising in vitro and in vivo anticancer activity. However, further development of this peptide was hampered by its degradation in biological fluids as well as by its low micromolar affinity for the receptor. Herein, extensive chemical modifications led to the development of a new analogue (10) with enhanced potency, specificity, and plasma stability. A combined approach of Ala-amino acid scan, NMR, and molecular modeling unraveled the reasons behind the improved binding properties of 10 vs 2. Biological investigations on leukemia (CEM) and colon (HT29 and HCT116) cancer cell lines showed that 10 is able to impair CXCL12-mediated cell migration, ERK-phosphorylation, and CXCR4 internalization. These outcomes might pave the way for the future preclinical development of 10 in CXCR4 overexpressing leukemia and colon cancer.
- Published
- 2016
- Full Text
- View/download PDF
45. Best Matching Protein Conformations and Docking Programs for a Virtual Screening Campaign Against SMO Receptor.
- Author
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Amendola G, Di Maio D, La Pietra V, and Cosconati S
- Subjects
- Algorithms, Humans, Ligands, Models, Molecular, Molecular Docking Simulation methods, Protein Binding physiology, Protein Conformation, Retrospective Studies, Software, Structure-Activity Relationship, Drug Discovery methods, Pharmaceutical Preparations chemistry, Smoothened Receptor antagonists & inhibitors
- Abstract
SMO receptor is one of the main components of the Hedgehog biochemical pathway. In the last decades compelling body of evidence demonstrated that this receptor is a pertinent target for the treatment of various types of solid tumors. Recently, the X-ray determination of the three-dimensional structure of SMO in complex with different antagonists opened up the way for the structure-based design of new antagonists for this receptor that could possibly overcome the limitations connected with the induction of acquired tumor resistance. Herein, taking advantage of three different docking software (namely Glide, PLANTS, and Vina) and of the available SMO structures we set up a retrospective virtual screening (VS) protocol. A database, made up by known SMO antagonists and compounds with no alleged activity against the receptor was created and screened against the different SMO structures. To evaluate the performance of the ranking in VS calculations different statistical metrics (EF, AUAC and BEDROC) were employed allowing to identify the best performing VS docking protocol. Results of these studies will serve as a platform for the application of structure-based VS against the pharmaceutically relevant SMO receptor., (© 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)
- Published
- 2016
- Full Text
- View/download PDF
46. Lead Optimization of 2-Phenylindolylglyoxylyldipeptide Murine Double Minute (MDM)2/Translocator Protein (TSPO) Dual Inhibitors for the Treatment of Gliomas.
- Author
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Daniele S, La Pietra V, Barresi E, Di Maro S, Da Pozzo E, Robello M, La Motta C, Cosconati S, Taliani S, Marinelli L, Novellino E, Martini C, and Da Settimo F
- Subjects
- Antineoplastic Agents chemical synthesis, Antineoplastic Agents chemistry, Cell Proliferation drug effects, Cell Survival drug effects, Dipeptides chemical synthesis, Dipeptides chemistry, Dose-Response Relationship, Drug, Drug Screening Assays, Antitumor, Glioblastoma pathology, Humans, Models, Molecular, Molecular Structure, Proto-Oncogene Proteins c-mdm2 metabolism, Structure-Activity Relationship, Tumor Cells, Cultured, Antineoplastic Agents pharmacology, Dipeptides pharmacology, Glioblastoma drug therapy, Proto-Oncogene Proteins c-mdm2 antagonists & inhibitors, Receptors, GABA metabolism
- Abstract
In glioblastoma multiforme (GBM), translocator protein (TSPO) and murine double minute (MDM)2/p53 complex represent two druggable targets. We recently reported the first dual binder 3 possessing a higher anticancer effect in GBM cells than the standards PK11195 1 or Nutlin-3 2 singularly applied. Herein, through a structure-activity relationship study, we developed derivatives 4-10 with improved potencies toward both TSPO and MDM2. As a result, compound 9: (i) reactivated the p53 functionality; (ii) inhibited the viability of two human GBM cells; (iii) impaired the proliferation of glioma cancer stem cells (CSCs), more resistant to chemotherapeutics and responsible of GBM recurrence; (iv) sensitized GBM cells and CSCs to the activity of temozolomide; (v) directed its effects preferentially toward tumor cells with respect to healthy ones. Thus, 9 may represent a promising cytotoxic agent, which is worthy of being further developed for a therapeutic approach against GBM, where the downstream p53 signaling is intact and TSPO is overexpressed.
- Published
- 2016
- Full Text
- View/download PDF
47. Site-directed Mutagenesis of Key Residues Unveiled a Novel Allosteric Site on Human Adenosine Kinase for Pyrrolobenzoxa(thia)zepinone Non-Nucleoside Inhibitors.
- Author
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Savi L, Brindisi M, Alfano G, Butini S, La Pietra V, Novellino E, Marinelli L, Lossani A, Focher F, Cavella C, Campiani G, and Gemma S
- Subjects
- Allosteric Site, Humans, Mutagenesis, Site-Directed, Adenosine Kinase metabolism, Azepines pharmacology, Nucleosides antagonists & inhibitors
- Abstract
Most nucleoside kinases, besides the catalytic domain, feature an allosteric domain which modulates their activity. Generally, non-substrate analogs, interacting with allosteric sites, represent a major opportunity for developing more selective and safer therapeutics. We recently developed a series of non-nucleoside non-competitive inhibitors of human adenosine kinase (hAK), based on a pyrrolobenzoxa(thia)zepinone scaffold. Based on computational analysis, we hypothesized the existence of a novel allosteric site on hAK, topographically distinct from the catalytic site. In this study, we have adopted a multidisciplinary approach including molecular modeling, biochemical studies, and site-directed mutagenesis to validate our hypothesis. Based on a three-dimensional model of interaction between hAK and our molecules, we designed, cloned, and expressed specific, single and double point mutants of hAK (Q74A, Q78A, H107A, K341A, F338A, and Q74A-F338A). Kinetic characterization of recombinant enzymes indicated that these mutations did not affect enzyme functioning; conversely, mutated enzymes are endowed of reduced susceptibility to our non-nucleoside inhibitors, while maintaining comparable affinity for nucleoside inhibitors to the wild-type enzyme. This study represents the first characterization and validation of a novel allosteric site in hAK and may pave the way to the development of novel selective and potent non-nucleoside inhibitors of hAK endowed with therapeutic potential., (© 2015 John Wiley & Sons A/S.)
- Published
- 2016
- Full Text
- View/download PDF
48. Development of novel dipeptide-like rhodesain inhibitors containing the 3-bromoisoxazoline warhead in a constrained conformation.
- Author
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Ettari R, Pinto A, Previti S, Tamborini L, Angelo IC, La Pietra V, Marinelli L, Novellino E, Schirmeister T, Zappalà M, Grasso S, De Micheli C, and Conti P
- Subjects
- Animals, Antiprotozoal Agents chemical synthesis, Antiprotozoal Agents pharmacology, Binding Sites, Cell Line, Cell Survival drug effects, Cysteine Endopeptidases metabolism, Cysteine Endopeptidases pharmacology, Cysteine Proteases chemistry, Cysteine Proteases metabolism, Cysteine Proteinase Inhibitors chemistry, Cysteine Proteinase Inhibitors metabolism, Cysteine Proteinase Inhibitors pharmacology, Dipeptides chemistry, Drug Design, Mice, Molecular Docking Simulation, Protein Structure, Tertiary, Structure-Activity Relationship, Trypanosoma brucei brucei drug effects, Antiprotozoal Agents chemistry, Cysteine Endopeptidases chemistry, Isoxazoles chemistry
- Abstract
Novel dipeptide-like rhodesain inhibitors containing the 3-bromoisoxazoline warhead in a constrained conformation were developed; some of them possess K(i) values in the micromolar range. We studied the structure-activity relationship of these derivatives and we performed docking studies, which allowed us to find out the key interactions established by the inhibitors with the target enzyme. Biological results indicate that the nature of the P2 and P3 substituents and their binding to the S2/S3 pockets is strictly interdependent., (Copyright © 2015 Elsevier Ltd. All rights reserved.)
- Published
- 2015
- Full Text
- View/download PDF
49. A novel cell-permeable, selective, and noncompetitive inhibitor of KAT3 histone acetyltransferases from a combined molecular pruning/classical isosterism approach.
- Author
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Milite C, Feoli A, Sasaki K, La Pietra V, Balzano AL, Marinelli L, Mai A, Novellino E, Castellano S, Tosco A, and Sbardella G
- Subjects
- Acetylation drug effects, Cell Cycle Checkpoints drug effects, Cell Line, Tumor, Cell Survival drug effects, Enzyme Inhibitors chemistry, Enzyme Inhibitors pharmacology, Histones metabolism, Humans, Leukemia drug therapy, Leukemia enzymology, Leukemia metabolism, Lysine metabolism, Models, Molecular, p300-CBP Transcription Factors metabolism, Antineoplastic Agents chemistry, Antineoplastic Agents pharmacology, p300-CBP Transcription Factors antagonists & inhibitors
- Abstract
Selective inhibitors of the two paralogue KAT3 acetyltransferases (CBP and p300) may serve not only as precious chemical tools to investigate the role of these enzymes in physiopathological mechanisms but also as lead structures for the development of further antitumor agents. After the application of a molecular pruning approach to the hardly optimizable and not very cell-permeable garcinol core structure, we prepared many analogues that were screened for their inhibitory effects using biochemical and biophysical (SPR) assays. Further optimization led to the discovery of the benzylidenebarbituric acid derivative 7h (EML425) as a potent and selective reversible inhibitor of CBP/p300, noncompetitive versus both acetyl-CoA and a histone H3 peptide, and endowed with good cell permeability. Furthermore, in human leukemia U937 cells, it induced a marked and time-dependent reduction in the acetylation of lysine H4K5 and H3K9, a marked arrest in the G0/G1 phase and a significant increase in the hypodiploid nuclei percentage.
- Published
- 2015
- Full Text
- View/download PDF
50. Structure-based lead optimization and biological evaluation of BAX direct activators as novel potential anticancer agents.
- Author
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Stornaiuolo M, La Regina G, Passacantilli S, Grassia G, Coluccia A, La Pietra V, Giustiniano M, Cassese H, Di Maro S, Brancaccio D, Taliani S, Ialenti A, Silvestri R, Martini C, Novellino E, and Marinelli L
- Subjects
- Animals, Apoptosis drug effects, Cell Survival drug effects, Cells, Cultured, Female, Fluorescent Antibody Technique, Humans, Immunoblotting, Immunoprecipitation, Jurkat Cells, Lung Neoplasms metabolism, Lung Neoplasms pathology, Mice, Mice, Inbred C57BL, Mice, Knockout, Mitochondria drug effects, Mitochondria metabolism, Models, Molecular, Structure-Activity Relationship, bcl-2-Associated X Protein physiology, Antineoplastic Agents chemistry, Antineoplastic Agents pharmacology, Drug Screening Assays, Antitumor, Hydrazones chemistry, Hydrazones pharmacology, Lung Neoplasms drug therapy, Pyrazoles chemistry, Pyrazoles pharmacology, bcl-2-Associated X Protein antagonists & inhibitors
- Abstract
The first direct activator of BAX, a pro-apoptotic member of the BCL-2 family, has been recently identified. Herein, a structure-based lead optimization turned out into a small series of analogues, where 8 is the most potent compound published so far. 8 was used as pharmacological tool to ascertain, for the first time, the anticancer potential of BAX direct activators and the obtained results would suggest that BAX direct activators are potential future anticancer drugs rather than venoms.
- Published
- 2015
- Full Text
- View/download PDF
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