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Start Over Author "Casale E" Topic cyclin-dependent kinases
4 results on '"Casale E"'

1. Identification of potent pyrazolo[4,3-h]quinazoline-3-carboxamides as multi-cyclin-dependent kinase inhibitors.

Author

Traquandi G, Ciomei M, Ballinari D, Casale E, Colombo N, Croci V, Fiorentini F, Isacchi A, Longo A, Mercurio C, Panzeri A, Pastori W, Pevarello P, Volpi D, Roussel P, Vulpetti A, and Brasca MG

Subjects
Animals, Antineoplastic Agents chemical synthesis, Antineoplastic Agents chemistry, Antineoplastic Agents pharmacokinetics, Area Under Curve, Cell Line, Tumor, Cell Proliferation drug effects, Cyclin-Dependent Kinases metabolism, Female, Half-Life, Inhibitory Concentration 50, Magnetic Resonance Spectroscopy, Mice, Mice, Inbred BALB C, Mice, Nude, Protein Kinase Inhibitors chemical synthesis, Protein Kinase Inhibitors chemistry, Protein Kinase Inhibitors pharmacokinetics, Pyrazoles chemical synthesis, Pyrazoles chemistry, Pyrazoles pharmacokinetics, Quinazolines chemical synthesis, Quinazolines chemistry, Quinazolines pharmacokinetics, Random Allocation, Spectrometry, Mass, Electrospray Ionization, Structure-Activity Relationship, Xenograft Model Antitumor Assays, Antineoplastic Agents pharmacology, Cyclin-Dependent Kinases antagonists & inhibitors, Ovarian Neoplasms drug therapy, Protein Kinase Inhibitors pharmacology, Pyrazoles pharmacology, Quinazolines pharmacology
Abstract

Abnormal proliferation mediated by disruption of the mechanisms that keep the cell cycle under control is a hallmark of virtually all cancer cells. Compounds targeting complexes between cyclin-dependent kinases (CDKs) and cyclins (Cy) and inhibiting their activity are regarded as promising antitumor agents to complement the existing therapies. An expansion of pyrazolo[4,3-h]quinazoline chemical class oriented to the development of three points of variability was undertaken leading to a series of compounds able to inhibit CDKs both in vitro and in vivo. Starting from the CDK selective but poorly soluble hit compound 1, we succeeded in obtaining several compounds showing enhanced inhibitory activity both on CDKs and on tumor cells and displaying improved physical properties and pharmacokinetic behavior. Our study led to the identification of compound 59 as a highly potent, orally bioavailable CDK inhibitor that exhibited significant in vivo efficacy on the A2780 ovarian carcinoma xenograft model. The demonstrated mechanisms of action of compound 59 on cancer cell lines and its ability to inhibit tumor growth in vivo render this compound very interesting as potential antineoplastic agent.

Published
2010
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2. Optimization of 6,6-dimethyl pyrrolo[3,4-c]pyrazoles: Identification of PHA-793887, a potent CDK inhibitor suitable for intravenous dosing.

Author

Brasca MG, Albanese C, Alzani R, Amici R, Avanzi N, Ballinari D, Bischoff J, Borghi D, Casale E, Croci V, Fiorentini F, Isacchi A, Mercurio C, Nesi M, Orsini P, Pastori W, Pesenti E, Pevarello P, Roussel P, Varasi M, Volpi D, Vulpetti A, and Ciomei M

Subjects
Animals, Antineoplastic Agents chemical synthesis, Antineoplastic Agents pharmacokinetics, Binding Sites, Cell Line, Tumor, Crystallography, X-Ray, Cyclin-Dependent Kinases metabolism, HCT116 Cells, Humans, Injections, Intravenous, Mice, Mice, Nude, Protein Kinase Inhibitors chemical synthesis, Protein Kinase Inhibitors pharmacokinetics, Pyrazoles chemical synthesis, Pyrazoles pharmacokinetics, Pyrroles chemical synthesis, Pyrroles pharmacokinetics, Xenograft Model Antitumor Assays, Antineoplastic Agents chemistry, Cyclin-Dependent Kinases antagonists & inhibitors, Protein Kinase Inhibitors chemistry, Pyrazoles chemistry, Pyrroles chemistry
Abstract

We have recently reported CDK inhibitors based on the 6-substituted pyrrolo[3,4-c]pyrazole core structure. Improvement of inhibitory potency against multiple CDKs, antiproliferative activity against cancer cell lines and optimization of the physico-chemical properties led to the identification of highly potent compounds. Compound 31 (PHA-793887) showed good efficacy in the human ovarian A2780, colon HCT-116 and pancreatic BX-PC3 carcinoma xenograft models and was well tolerated upon daily treatments by iv administration. It was identified as a drug candidate for clinical evaluation in patients with solid tumors., (Copyright 2010 Elsevier Ltd. All rights reserved.)

Published
2010
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3. Identification of N,1,4,4-tetramethyl-8-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide (PHA-848125), a potent, orally available cyclin dependent kinase inhibitor.

Author

Brasca MG, Amboldi N, Ballinari D, Cameron A, Casale E, Cervi G, Colombo M, Colotta F, Croci V, D'Alessio R, Fiorentini F, Isacchi A, Mercurio C, Moretti W, Panzeri A, Pastori W, Pevarello P, Quartieri F, Roletto F, Traquandi G, Vianello P, Vulpetti A, and Ciomei M

Subjects
Administration, Oral, Animals, Antineoplastic Agents pharmacokinetics, Antineoplastic Agents pharmacology, Cell Proliferation drug effects, Crystallography, X-Ray, Drug Screening Assays, Antitumor, Humans, Male, Mice, Mice, Nude, Models, Molecular, Neoplasm Transplantation, Pyrazoles pharmacokinetics, Pyrazoles pharmacology, Quinazolines pharmacokinetics, Quinazolines pharmacology, Solubility, Structure-Activity Relationship, Transplantation, Heterologous, Antineoplastic Agents chemical synthesis, Cyclin-Dependent Kinases antagonists & inhibitors, Pyrazoles chemical synthesis, Quinazolines chemical synthesis
Abstract

The discovery of a novel class of inhibitors of cyclin dependent kinases (CDKs) is described. Starting from compound 1, showing good potency as inhibitor of CDKs but being poorly selective against a panel of serine-threonine and tyrosine kinases, new analogues were synthesized. Enhancement in selectivity, antiproliferative activity against A2780 human ovarian carcinoma cells, and optimization of the physical properties and pharmacokinetic profile led to the identification of highly potent and orally available compounds. Compound 28 (PHA-848125), which in the preclinical xenograft A2780 human ovarian carcinoma model showed good efficacy and was well tolerated upon repeated daily treatments, was identified as a drug candidate for further development. Compound 28 is currently undergoing phase I and phase II clinical trials.

Published
2009
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4. Identification of potent pyrazolo[4,3-h]quinazoline-3-carboxamides as multi-cyclin-dependent kinase inhibitors

Author

Achille Panzeri, Wilma Pastori, Gabriella Traquandi, Daniele Volpi, Anna Vulpetti, Elena Casale, Francesco Fiorentini, Nicoletta Colombo, Antonio Longo, Valter Croci, Maria Gabriella Brasca, Marina Ciomei, Dario Ballinari, Patrick Roussel, Antonella Isacchi, Paolo Pevarello, Ciro Mercurio, Traquandi, G, Ciomei, M, Ballinari, D, Casale, E, Colombo, N, Croci, V, Fiorentini, F, Isacchi, A, Longo, A, Mercurio, C, Panzeri, A, Pastori, W, Pevarello, P, Volpi, D, Roussel, P, Vulpetti, A, and Brasca, M

Subjects
Spectrometry, Mass, Electrospray Ionization, Magnetic Resonance Spectroscopy, Mice, Nude, Antineoplastic Agents, Pharmacology, Inhibitory Concentration 50, Mice, Random Allocation, Structure-Activity Relationship, chemistry.chemical_compound, Cyclin-dependent kinase, In vivo, Cell Line, Tumor, Drug Discovery, Quinazoline, Animals, Structure–activity relationship, kinase inhibitors, Protein Kinase Inhibitors, Cell Proliferation, Ovarian Neoplasms, Mice, Inbred BALB C, biology, Kinase, Cell cycle, Xenograft Model Antitumor Assays, Cyclin-Dependent Kinases, chemistry, Area Under Curve, Cancer cell, Quinazolines, biology.protein, Pyrazoles, Molecular Medicine, Female, CDK inhibitor, Half-Life
Abstract

Abnormal proliferation mediated by disruption of the mechanisms that keep the cell cycle under control is a hallmark of virtually all cancer cells. Compounds targeting complexes between cyclin-dependent kinases (CDKs) and cyclins (Cy) and inhibiting their activity are regarded as promising antitumor agents to complement the existing therapies. An expansion of pyrazolo[4,3-h]quinazoline chemical class oriented to the development of three points of variability was undertaken leading to a series of compounds able to inhibit CDKs both in vitro and in vivo. Starting from the CDK selective but poorly soluble hit compound 1, we succeeded in obtaining several compounds showing enhanced inhibitory activity both on CDKs and on tumor cells and displaying improved physical properties and pharmacokinetic behavior. Our study led to the identification of compound 59 as a highly potent, orally bioavailable CDK inhibitor that exhibited significant in vivo efficacy on the A2780 ovarian carcinoma xenograft model. The demonstrated mechanisms of action of compound 59 on cancer cell lines and its ability to inhibit tumor growth in vivo render this compound very interesting as potential antineoplastic agent. © 2010 American Chemical Society.

Published
2010

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