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

Maria Gabriella Brasca; Nadia Amboldi; Dario Ballinari; Alexander Cameron; Elena Casale; Giovanni Cervi; Maristella Colombo; Francesco Colotta; Valter Croci; Roberto D'Alessio; Francesco Fiorentini; Antonella Isacchi; Ciro Mercurio; Walter Moretti; Achille Panzeri; Wilma Pastori; Paolo Pevarello; Francesca Quartieri; Fulvia Roletto; Gabriella Traquandi; Paola Vianello; Anna Vulpetti; Marina Ciomei

doi:10.1021/jm9006559

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

Maria Gabriella Brasca, Nadia Amboldi, Dario Ballinari, Alexander Cameron, Elena Casale, Giovanni Cervi, Maristella Colombo, Francesco Colotta, Valter Croci, Roberto D'Alessio, Francesco Fiorentini, Antonella Isacchi, Ciro Mercurio, Walter Moretti, Achille Panzeri, Wilma Pastori, Paolo Pevarello, Francesca Quartieri, Fulvia Roletto, Gabriella TraquandiPaola Vianello, Anna Vulpetti, Marina Ciomei

Istituto Europeo di Oncologia

Research output: Contribution to journal › Article › peer-review

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.

Original language	English
Pages (from-to)	5152-5163
Number of pages	12
Journal	Journal of Medicinal Chemistry
Volume	52
Issue number	16
DOIs	https://doi.org/10.1021/jm9006559
Publication status	Published - Aug 27 2009

ASJC Scopus subject areas

Molecular Medicine
Drug Discovery

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Brasca, M. G., 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., ... Ciomei, M. (2009). 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. Journal of Medicinal Chemistry, 52(16), 5152-5163. https://doi.org/10.1021/jm9006559

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. / Brasca, Maria Gabriella; Amboldi, Nadia; Ballinari, Dario; Cameron, Alexander; Casale, Elena; Cervi, Giovanni; Colombo, Maristella; Colotta, Francesco; Croci, Valter; D'Alessio, Roberto; Fiorentini, Francesco; Isacchi, Antonella; Mercurio, Ciro; Moretti, Walter; Panzeri, Achille; Pastori, Wilma; Pevarello, Paolo; Quartieri, Francesca; Roletto, Fulvia; Traquandi, Gabriella; Vianello, Paola; Vulpetti, Anna; Ciomei, Marina.

In: Journal of Medicinal Chemistry, Vol. 52, No. 16, 27.08.2009, p. 5152-5163.

Research output: Contribution to journal › Article › peer-review

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 & Ciomei, M 2009, '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', Journal of Medicinal Chemistry, vol. 52, no. 16, pp. 5152-5163. https://doi.org/10.1021/jm9006559

Brasca MG, Amboldi N, Ballinari D, Cameron A, Casale E, Cervi G et al. 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. Journal of Medicinal Chemistry. 2009 Aug 27;52(16):5152-5163. https://doi.org/10.1021/jm9006559

Brasca, Maria Gabriella ; Amboldi, Nadia ; Ballinari, Dario ; Cameron, Alexander ; Casale, Elena ; Cervi, Giovanni ; Colombo, Maristella ; Colotta, Francesco ; Croci, Valter ; D'Alessio, Roberto ; Fiorentini, Francesco ; Isacchi, Antonella ; Mercurio, Ciro ; Moretti, Walter ; Panzeri, Achille ; Pastori, Wilma ; Pevarello, Paolo ; Quartieri, Francesca ; Roletto, Fulvia ; Traquandi, Gabriella ; Vianello, Paola ; Vulpetti, Anna ; Ciomei, Marina. / 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. In: Journal of Medicinal Chemistry. 2009 ; Vol. 52, No. 16. pp. 5152-5163.

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