15 results on '"Biancofiore, I"'
Search Results
2. KEAP1 IN COMPLEX WITH COMPOUND 23
- Author
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Ontoria, J.M., primary, Biancofiore, I., additional, Fezzardi, P., additional, Torrente de Haro, E., additional, Colarusso, S., additional, Bianchi, E., additional, Andreini, M., additional, Patsilinakos, A., additional, Summa, V., additional, Pacifici, R., additional, Munoz-Sanjuan, I., additional, Park, L., additional, Bresciani, A., additional, Dominguez, C., additional, Toledo-Sherman, L., additional, and Harper, S., additional
- Published
- 2020
- Full Text
- View/download PDF
3. Combined Peptide and Small-Molecule Approach toward Nonacidic THIQ Inhibitors of the KEAP1/NRF2 Interaction
- Author
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Georg Kempf, Ignacio Munoz-Sanjuan, Alexandros Patsilinakos, Matteo Andreini, Stefania Colarusso, Vincenzo Summa, Jesus Maria Ontoria Ontoria, Federica Ferrigno, Paola Fezzardi, Steven J. Harper, Leticia Toledo Sherman, Stefan Steinbacher, Ilaria Biancofiore, Esther Torrente, Martin Augustin, Elisabetta Bianchi, Larry Park, Alberto Bresciani, Robert Pacifici, Celia Dominguez, Ontoria, J. M., Biancofiore, I., Fezzardi, P., Ferrigno, F., Torrente, E., Colarusso, S., Bianchi, E., Andreini, M., Patsilinakos, A., Kempf, G., Augustin, M., Steinbacher, S., Summa, V., Pacifici, R., Munoz-Sanjuan, I., Park, L., Bresciani, A., Dominguez, C., Sherman, L. T., and Harper, S.
- Subjects
chemistry.chemical_classification ,Chemistry ,Tetrahydroisoquinoline ,Organic Chemistry ,Huntington's disease ,Peptide ,respiratory system ,digestive system ,environment and public health ,Biochemistry ,KEAP1 ,Small molecule ,Keap1 nrf2 ,NRF2 ,Protein–protein interaction ,Negative regulator ,protein-protein interaction ,chemistry.chemical_compound ,THIQ ,Drug Discovery ,Biophysics ,medicine ,tetrahydroisoquinoline ,medicine.drug - Abstract
[Image: see text] The NRF2-ARE pathway is an intrinsic mechanism of defense against oxidative stress. Inhibition of the interaction between NRF2 and its main negative regulator KEAP1 is an attractive strategy toward neuroprotective agents. We report here the identification of nonacidic tetrahydroisoquinolines (THIQs) that inhibit the KEAP1/NRF2 protein–protein interaction. Peptide SAR at one residue is utilized as a tool to probe structural changes within a specific pocket of the KEAP1 binding site. We used structural information from peptide screening at the P2 pocket, noncovalent small-molecules inhibitors, and the outcome from an explorative SAR at position 5 of THIQs to identify a series of neutral THIQ analogs that bind to KEAP1 in the low micromolar range. These analogs establish new H-bond interactions at the P3 and P2 pockets allowing the replacement of the carboxylic acid functionality by a neutral primary carboxamide. X-ray crystallographic studies reveal the novel binding mode of these molecules to KEAP1.
- Published
- 2020
4. Improved Selective Class I HDAC and Novel Selective HDAC3 Inhibitors: Beyond Hydroxamic Acids and Benzamides
- Author
-
Annalise Di Marco, Alberto Bresciani, Simona Ponzi, Antonella Cellucci, Jesus Maria Ontoria Ontoria, Alina Ciammaichella, Alessandra Francone, Steven J. Harper, Savina Malancona, Maria Veneziano, Vincenzo Summa, Edith Monteagudo, Federica Ferrigno, Emanuela Nizi, Ilaria Biancofiore, Ilaria Rossetti, Paola Pace, Bresciani, A., Ontoria, J. M., Biancofiore, I., Cellucci, A., Ciammaichella, A., Di Marco, A., Ferrigno, F., Francone, A., Malancona, S., Monteagudo, E., Nizi, E., Pace, P., Ponzi, S., Rossetti, I., Veneziano, M., Summa, V., and Harper, S.
- Subjects
HDAC3 selective ,Hydroxamic acid ,Zinc binding ,nonbenzamide ,010405 organic chemistry ,Organic Chemistry ,HDAC3 ,01 natural sciences ,Biochemistry ,Combinatorial chemistry ,0104 chemical sciences ,010404 medicinal & biomolecular chemistry ,chemistry.chemical_compound ,chemistry ,Drug Discovery ,Histone deacetylase ,nonhydroxamate - Abstract
[Image: see text] The application of class I HDAC inhibitors as cancer therapies is well established, but more recently their development for nononcological indications has increased. We report here on the generation of improved class I selective human HDAC inhibitors based on an ethylketone zinc binding group (ZBG) in place of the hydroxamic acid that features the majority of HDAC inhibitors. We also describe a novel set of HDAC3 isoform selective inhibitors that show stronger potency and selectivity than the most commonly used HDAC3 selective tool compound RGFP966. These compounds are again based on an alternative ZBG with respect to the ortho-anilide that is featured in HDAC3 selective compounds reported to date.
- Published
- 2018
5. Optimization of 2-(1H-imidazo-2-yl)piperazines series of Trypanosoma brucei growth inhibitors as potential treatment for the second stage of HAT
- Author
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Nadia Gennari, Maria Vittoria Orsale, Vincenzo Summa, Rita Graziani, Simona Ponzi, Jesus Maria Ontoria Ontoria, Alina Ciammaichella, Steven J. Harper, Andreina Basta, Giacomo Paonessa, Ilaria Biancofiore, Valentina Nardi, Federica Ferrigno, Ivan Fini, Melania D'Amico, Ciammaichella, A., Ferrigno, F., Basta, A., D'Amico, M., Biancofiore, I., Nardi, V., Ponzi, S., Graziani, R., Gennari, N., Vittoria Orsale, M., Fini, I., Paonessa, G., Summa, V., Harper, S., and Ontoria, J. M.
- Subjects
Antiparasitic ,Cell Survival ,medicine.drug_class ,Morpholines ,Trypanosoma brucei brucei ,Clinical Biochemistry ,Drug Evaluation, Preclinical ,Pharmaceutical Science ,Pharmacology ,Trypanosoma brucei ,01 natural sciences ,Biochemistry ,Piperazines ,Structure-Activity Relationship ,Isomerism ,In vivo ,Sleeping sickne ,Drug Discovery ,Human Umbilical Vein Endothelial Cells ,medicine ,Humans ,African trypanosomiasis ,Molecular Biology ,biology ,010405 organic chemistry ,Chemistry ,Organic Chemistry ,medicine.disease ,biology.organism_classification ,Human African Trypanosomiasis (HAT) ,Trypanocidal Agents ,Growth Inhibitors ,0104 chemical sciences ,010404 medicinal & biomolecular chemistry ,Trypanosomiasis, African ,Quinolines ,Molecular Medicine - Abstract
A previous publication from our laboratory reported the identification of a new class of 2-(1H-imidazo-2-yl)piperazines as potent T. brucei growth inhibitors as potential treatment for Human African Trypanosomiasis (HAT). This work describes the structure–activity relationship (SAR) around the hit compound 1, which led to the identification of the optimized compound 18, a single digit nanomolar inhibitor (EC50 7 nM), not cytotoxic and with optimal in vivo profile that made it a suitable candidate for efficacy studies in a mouse model mimicking the second stage of disease.
- Published
- 2020
6. Discovery of 2-(1H-imidazo-2-yl)piperazines as a new class of potent and non-cytotoxic inhibitors of Trypanosoma brucei growth in vitro
- Author
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Annalise Di Marco, Steven J. Harper, Savina Malancona, Nadia Gennari, Simona Ponzi, Jesus Maria Ontoria Ontoria, Marcel Kaiser, Rita Graziani, Ilaria Biancofiore, Giacomo Paonessa, Alberto Bresciani, Federica Ferrigno, Vincenzo Summa, Ferrigno, F., Biancofiore, I., Malancona, S., Ponzi, S., Paonessa, G., Graziani, R., Bresciani, A., Gennari, N., Di Marco, A., Kaiser, M., Summa, V., Harper, S., and Ontoria, J. M.
- Subjects
0301 basic medicine ,Antiparasitic ,medicine.drug_class ,030106 microbiology ,Clinical Biochemistry ,Plasmodium falciparum ,Trypanosoma brucei brucei ,Pharmaceutical Science ,Trypanosoma brucei ,HeLa Cell ,Biochemistry ,Piperazines ,03 medical and health sciences ,chemistry.chemical_compound ,Structure-Activity Relationship ,Sleeping sickne ,parasitic diseases ,Drug Discovery ,medicine ,Cytotoxic T cell ,Humans ,African trypanosomiasis ,Malaria, Falciparum ,Trypanosoma cruzi ,Molecular Biology ,Imidazole ,Piperazine ,biology ,2-(1H-imidazo-2-yl)piperazine ,Trypanocidal Agent ,Organic Chemistry ,Imidazoles ,Trypanosoma brucei rhodesiense ,medicine.disease ,biology.organism_classification ,Human African Trypanosomiasis (HAT) ,Virology ,Trypanocidal Agents ,030104 developmental biology ,Trypanosomiasis, African ,chemistry ,Molecular Medicine ,Growth inhibition ,Human ,HeLa Cells - Abstract
The identification of a new series of growth inhibitors of Trypanosoma brucei rhodesiense, causative agent of Human African Trypanosomiasis (HAT), is described. A selection of compounds from our in-house compound collection was screened in vitro against the parasite leading to the identification of compounds with nanomolar inhibition of T. brucei growth. Preliminary SAR on the hit compound led to the identification of compound 34 that shows low nanomolar parasite growth inhibition (T. brucei EC50 5 nM), is not cytotoxic (HeLa CC50 > 25,000 nM) and is selective over other parasites, such as Trypanosoma cruzi and Plasmodium falciparum (T. cruzi EC50 8120 nM, P. falciparum EC50 3624 nM).
- Published
- 2018
7. Discovery of a Selective Series of Inhibitors of Plasmodium falciparum HDACs
- Author
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Nadia Gennari, Emanuela Nizi, Steven J. Harper, Savina Malancona, Sergio Altamura, Edith Monteagudo, David Roberts, Ilaria Biancofiore, Paul Willis, Maria Vittoria Orsale, Ottavia Cecchetti, Antonella Cellucci, Ralph Laufer, Rita Graziani, Alberto Bresciani, Simona Ponzi, Jesus Maria Ontoria Ontoria, Maria Veneziano, Annalise Di Marco, Giacomo Paonessa, Vincenzo Summa, Federica Ferrigno, Ontoriajm, G Paonessa, G, Ponzi, S, Ferrigno, F, Nizi, E, Biancofiore, I, Malancona, S, Graziani, R, Roberts, D, Willis, P, Bresciani, A, Nadia Gennari, N, Cecchetti, O, Monteagudo, E, Orsale, Mv, Veneziano, M, Di Marco, A, Cellucci, A, Laufer, R, Sergio Altamura, S, Summa, V, and Harper, S
- Subjects
0301 basic medicine ,biology ,Chemistry ,030106 microbiology ,Organic Chemistry ,Growth inhibitory ,Plasmodium falciparum ,biology.organism_classification ,Biochemistry ,03 medical and health sciences ,030104 developmental biology ,Mechanism of action ,Drug Discovery ,medicine ,medicine.symptom - Abstract
The identification of a new series of P. falciparum growth inhibitors is described. Starting from a series of known human class I HDAC inhibitors a SAR exploration based on growth inhibitory activity in parasite and human cells-based assays led to the identification of compounds with submicromolar inhibition of P. falciparum growth (EC50500 nM) and good selectivity over the activity of human HDAC in cells (up to50-fold). Inhibition of parasital HDACs as the mechanism of action of this new class of selective growth inhibitors is supported by hyperacetylation studies.
- Published
- 2015
8. Deep Learning Approach for the Discovery of Tumor-Targeting Small Organic Ligands from DNA-Encoded Chemical Libraries.
- Author
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Torng W, Biancofiore I, Oehler S, Xu J, Xu J, Watson I, Masina B, Prati L, Favalli N, Bassi G, Neri D, Cazzamalli S, and Feng JA
- Abstract
DNA-Encoded Chemical Libraries (DELs) have emerged as efficient and cost-effective ligand discovery tools, which enable the generation of protein-ligand interaction data of unprecedented size. In this article, we present an approach that combines DEL screening and instance-level deep learning modeling to identify tumor-targeting ligands against carbonic anhydrase IX (CAIX), a clinically validated marker of hypoxia and clear cell renal cell carcinoma. We present a new ligand identification and hit-to-lead strategy driven by machine learning models trained on DELs, which expand the scope of DEL-derived chemical motifs. CAIX-screening datasets obtained from three different DELs were used to train machine learning models for generating novel hits, dissimilar to elements present in the original DELs. Out of the 152 novel potential hits that were identified with our approach and screened in an in vitro enzymatic inhibition assay, 70% displayed submicromolar activities (IC
50 < 1 μM). To generate lead compounds that are functionalized with anticancer payloads, analogues of top hits were prioritized for synthesis based on the predicted CAIX affinity and synthetic feasibility. Three lead candidates showed accumulation on the surface of CAIX-expressing tumor cells in cellular binding assays. The best compound displayed an in vitro KD of 5.7 nM and selectively targeted tumors in mice bearing human renal cell carcinoma lesions. Our results demonstrate the synergy between DEL and machine learning for the identification of novel hits and for the successful translation of lead candidates for in vivo targeting applications., Competing Interests: The authors declare the following competing financial interest(s): D.N. is the cofounder, C.E.O. and C.S.O. of Philogen S.p.A.. I.B., S.O., L.P., G.B., N.F. and S.C. are employees of Philochem AG, the Research and Development unit of the Philogen group. B.M. performed work related to this article during his internship at Philochem AG. W.T., J.X., I.W., J.F. are current or former employees at Google LLC., (© 2023 The Authors. Published by American Chemical Society.)- Published
- 2023
- Full Text
- View/download PDF
9. An ultra-high-affinity small organic ligand of fibroblast activation protein for tumor-targeting applications.
- Author
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Millul J, Bassi G, Mock J, Elsayed A, Pellegrino C, Zana A, Dakhel Plaza S, Nadal L, Gloger A, Schmidt E, Biancofiore I, Donckele EJ, Samain F, Neri D, and Cazzamalli S
- Subjects
- Animals, Cell Line, Tumor, Endopeptidases physiology, Fibroblasts, Gene Expression genetics, Gene Expression Regulation, Neoplastic genetics, Isotope Labeling, Ligands, Lutetium chemistry, Male, Membrane Proteins physiology, Mice, Mice, Nude, Neoplasms metabolism, Quinolines chemistry, Radioisotopes chemistry, Radiopharmaceuticals, Tissue Distribution physiology, Xenograft Model Antitumor Assays methods, Drug Delivery Systems methods, Endopeptidases chemistry, Endopeptidases metabolism, Membrane Proteins chemistry, Membrane Proteins metabolism
- Abstract
We describe the development of OncoFAP, an ultra-high-affinity ligand of fibroblast activation protein (FAP) for targeting applications with pan-tumoral potential. OncoFAP binds to human FAP with affinity in the subnanomolar concentration range and cross-reacts with the murine isoform of the protein. We generated various fluorescent and radiolabeled derivatives of OncoFAP in order to study biodistribution properties and tumor-targeting performance in preclinical models. Fluorescent derivatives selectively localized in FAP-positive tumors implanted in nude mice with a rapid and homogeneous penetration within the neoplastic tissue. Quantitative in vivo biodistribution studies with a lutetium-177-labeled derivative of OncoFAP revealed a preferential localization in tumors at doses of up to 1,000 nmol/kg. More than 30% of the injected dose had already accumulated in 1 g of tumor 10 min after intravenous injection and persisted for at least 3 h with excellent tumor-to-organ ratios. OncoFAP also served as a modular component for the generation of nonradioactive therapeutic products. A fluorescein conjugate mediated a potent and FAP-dependent tumor cell killing activity in combination with chimeric antigen receptor (CAR) T cells specific to fluorescein. Similarly, a conjugate of OncoFAP with the monomethyl auristatin E-based Vedotin payload was well tolerated and cured tumor-bearing mice in combination with a clinical-stage antibody-interleukin-2 fusion. Collectively, these data support the development of OncoFAP-based products for tumor-targeting applications in patients with cancer., Competing Interests: Competing interest statement: D.N. is a cofounder and shareholder of Philogen (http://www.philogen.com/en/), a Swiss-Italian Biotech company that operates in the field of ligand-based pharmacodelivery. J. Millul, G.B., J. Mock, A.Z., S.D.P., L.N., A.G., E.S., I.B., E.J.D., F.S., and S.C. are employees of Philochem AG, the daughter company of Philogen, acting as the discovery unit of the group.
- Published
- 2021
- Full Text
- View/download PDF
10. Optimization of 2-(1H-imidazo-2-yl)piperazines series of Trypanosoma brucei growth inhibitors as potential treatment for the second stage of HAT.
- Author
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Ciammaichella A, Ferrigno F, Basta A, D'Amico M, Biancofiore I, Nardi V, Ponzi S, Graziani R, Gennari N, Vittoria Orsale M, Fini I, Paonessa G, Summa V, Harper S, and Ontoria JM
- Subjects
- Cell Survival drug effects, Drug Evaluation, Preclinical, Growth Inhibitors pharmacology, Human Umbilical Vein Endothelial Cells, Humans, Isomerism, Morpholines chemistry, Piperazines pharmacology, Quinolines chemistry, Structure-Activity Relationship, Trypanocidal Agents pharmacology, Growth Inhibitors chemistry, Piperazines chemistry, Trypanocidal Agents chemistry, Trypanosoma brucei brucei drug effects, Trypanosomiasis, African drug therapy
- Abstract
A previous publication from our laboratory reported the identification of a new class of 2-(1H-imidazo-2-yl)piperazines as potent T. brucei growth inhibitors as potential treatment for Human African Trypanosomiasis (HAT). This work describes the structure-activity relationship (SAR) around the hit compound 1, which led to the identification of the optimized compound 18, a single digit nanomolar inhibitor (EC
50 7 nM), not cytotoxic and with optimal in vivo profile that made it a suitable candidate for efficacy studies in a mouse model mimicking the second stage of disease., 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 © 2020 Elsevier Ltd. All rights reserved.)- Published
- 2020
- Full Text
- View/download PDF
11. Combined Peptide and Small-Molecule Approach toward Nonacidic THIQ Inhibitors of the KEAP1/NRF2 Interaction.
- Author
-
Ontoria JM, Biancofiore I, Fezzardi P, Ferrigno F, Torrente E, Colarusso S, Bianchi E, Andreini M, Patsilinakos A, Kempf G, Augustin M, Steinbacher S, Summa V, Pacifici R, Muñoz-Sanjuan I, Park L, Bresciani A, Dominguez C, Sherman LT, and Harper S
- Abstract
The NRF2-ARE pathway is an intrinsic mechanism of defense against oxidative stress. Inhibition of the interaction between NRF2 and its main negative regulator KEAP1 is an attractive strategy toward neuroprotective agents. We report here the identification of nonacidic tetrahydroisoquinolines (THIQs) that inhibit the KEAP1/NRF2 protein-protein interaction. Peptide SAR at one residue is utilized as a tool to probe structural changes within a specific pocket of the KEAP1 binding site. We used structural information from peptide screening at the P2 pocket, noncovalent small-molecules inhibitors, and the outcome from an explorative SAR at position 5 of THIQs to identify a series of neutral THIQ analogs that bind to KEAP1 in the low micromolar range. These analogs establish new H-bond interactions at the P3 and P2 pockets allowing the replacement of the carboxylic acid functionality by a neutral primary carboxamide. X-ray crystallographic studies reveal the novel binding mode of these molecules to KEAP1., Competing Interests: The authors declare no competing financial interest., (Copyright © 2020 American Chemical Society.)
- Published
- 2020
- Full Text
- View/download PDF
12. Sulphide as a leaving group: highly stereoselective bromination of alkyl phenyl sulphides.
- Author
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Canestrari D, Cioffi C, Biancofiore I, Lancianesi S, Ghisu L, Ruether M, O'Brien J, Adamo MFA, and Ibrahim H
- Abstract
A conceptionally novel nucleophilic substitution approach to synthetically important alkyl bromides is presented. Using molecular bromine (Br
2 ), readily available secondary benzyl and tertiary alkyl phenyl sulphides are converted into the corresponding bromides under exceptionally mild, acid- and base-free reaction conditions. This simple transformation allows the isolation of elimination sensitive benzylic β-bromo carbonyl and nitrile compounds in mostly high yields and purities. Remarkably, protic functionalities such as acids and alcohols are tolerated. Enantioenriched benzylic β-sulphido esters, readily prepared by asymmetric sulpha-Michael addition, produce the corresponding inverted bromides with high stereoselectivities, approaching complete enantiospecificity at -40 °C. Significantly, the reported benzylic β-bromo esters can be stored without racemisation for prolonged periods at -20 °C. Their synthetic potential was demonstrated by the one-pot preparation of γ-azido alcohol ( S )- 5 in 90% ee. NMR studies revealed an initial formation of a sulphide bromine adduct, which in turn is in equilibrium with a postulated dibromosulphurane intermediate that undergoes C-Br bond formation., (This journal is © The Royal Society of Chemistry 2019.)- Published
- 2019
- Full Text
- View/download PDF
13. Discovery of 2-(1H-imidazo-2-yl)piperazines as a new class of potent and non-cytotoxic inhibitors of Trypanosoma brucei growth in vitro.
- Author
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Ferrigno F, Biancofiore I, Malancona S, Ponzi S, Paonessa G, Graziani R, Bresciani A, Gennari N, Di Marco A, Kaiser M, Summa V, Harper S, and Ontoria JM
- Subjects
- HeLa Cells, Humans, Imidazoles chemistry, Imidazoles pharmacology, Malaria, Falciparum drug therapy, Plasmodium falciparum drug effects, Structure-Activity Relationship, Trypanosoma brucei brucei growth & development, Trypanosomiasis, African parasitology, Piperazines chemistry, Piperazines pharmacology, Trypanocidal Agents chemistry, Trypanocidal Agents pharmacology, Trypanosoma brucei brucei drug effects, Trypanosomiasis, African drug therapy
- Abstract
The identification of a new series of growth inhibitors of Trypanosoma brucei rhodesiense, causative agent of Human African Trypanosomiasis (HAT), is described. A selection of compounds from our in-house compound collection was screened in vitro against the parasite leading to the identification of compounds with nanomolar inhibition of T. brucei growth. Preliminary SAR on the hit compound led to the identification of compound 34 that shows low nanomolar parasite growth inhibition (T. brucei EC
50 5 nM), is not cytotoxic (HeLa CC50 > 25,000 nM) and is selective over other parasites, such as Trypanosoma cruzi and Plasmodium falciparum (T. cruzi EC50 8120 nM, P. falciparum EC50 3624 nM)., (Copyright © 2018 Elsevier Ltd. All rights reserved.)- Published
- 2018
- Full Text
- View/download PDF
14. Improved Selective Class I HDAC and Novel Selective HDAC3 Inhibitors: Beyond Hydroxamic Acids and Benzamides.
- Author
-
Bresciani A, Ontoria JM, Biancofiore I, Cellucci A, Ciammaichella A, Di Marco A, Ferrigno F, Francone A, Malancona S, Monteagudo E, Nizi E, Pace P, Ponzi S, Rossetti I, Veneziano M, Summa V, and Harper S
- Abstract
The application of class I HDAC inhibitors as cancer therapies is well established, but more recently their development for nononcological indications has increased. We report here on the generation of improved class I selective human HDAC inhibitors based on an ethylketone zinc binding group (ZBG) in place of the hydroxamic acid that features the majority of HDAC inhibitors. We also describe a novel set of HDAC3 isoform selective inhibitors that show stronger potency and selectivity than the most commonly used HDAC3 selective tool compound RGFP966. These compounds are again based on an alternative ZBG with respect to the ortho -anilide that is featured in HDAC3 selective compounds reported to date., Competing Interests: The authors declare no competing financial interest.
- Published
- 2018
- Full Text
- View/download PDF
15. Discovery of a Selective Series of Inhibitors of Plasmodium falciparum HDACs.
- Author
-
Ontoria JM, Paonessa G, Ponzi S, Ferrigno F, Nizi E, Biancofiore I, Malancona S, Graziani R, Roberts D, Willis P, Bresciani A, Gennari N, Cecchetti O, Monteagudo E, Orsale MV, Veneziano M, Di Marco A, Cellucci A, Laufer R, Altamura S, Summa V, and Harper S
- Abstract
The identification of a new series of P. falciparum growth inhibitors is described. Starting from a series of known human class I HDAC inhibitors a SAR exploration based on growth inhibitory activity in parasite and human cells-based assays led to the identification of compounds with submicromolar inhibition of P. falciparum growth (EC50 < 500 nM) and good selectivity over the activity of human HDAC in cells (up to >50-fold). Inhibition of parasital HDACs as the mechanism of action of this new class of selective growth inhibitors is supported by hyperacetylation studies.
- Published
- 2016
- Full Text
- View/download PDF
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