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

Gabriella Traquandi, Marina Ciomei, Dario Ballinari, Elena Casale, Nicoletta Colombo, Valter Croci, Francesco Fiorentini, Antonella Isacchi, Antonio Longo, Ciro Mercurio, Achille Panzeri, Wilma Pastori, Paolo Pevarello, Daniele Volpi, Patrick Roussel, Anna Vulpetti, Maria Gabriella Brasca

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish
Pages (from-to)2171-2187
Number of pages17
JournalJournal of Medicinal Chemistry
Issue number5
Publication statusPublished - Mar 11 2010

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery


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