Discovery of 8-cyclopentyl-2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-7- oxo-7,8-dihydro-pyrido[2,3- d ]pyrimidine-6-carbonitrile (7x) as a potent inhibitor of cyclin-dependent kinase 4 (CDK4) and AMPK-related kinase 5 (ARK5)

M. V.Ramana Reddy, Balireddy Akula, Stephen C. Cosenza, Saikrishna Athuluridivakar, Muralidhar R. Mallireddigari, Venkat R. Pallela, Vinay K. Billa, D. R.C.Venkata Subbaiah, E. Vijaya Bharathi, Rodrigo Vasquez-Del Carpio, Amol Padgaonkar, Stacey J. Baker, E. Premkumar Reddy

Research output: Contribution to journalArticle

39 Scopus citations

Abstract

The success of imatinib, a BCR-ABL inhibitor for the treatment of chronic myelogenous leukemia, has created a great impetus for the development of additional kinase inhibitors as therapeutic agents. However, the complexity of cancer has led to recent interest in polypharmacological approaches for developing multikinase inhibitors with low toxicity profiles. With this goal in mind, we analyzed more than 150 novel cyano pyridopyrimidine compounds and identified structure-activity relationship trends that can be exploited in the design of potent kinase inhibitors. One compound, 8-cyclopentyl-2-[4-(4-methyl- piperazin-1-yl)-phenylamino]-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidine-6- carbonitrile (7x), was found to be the most active, inducing apoptosis of tumor cells at a concentration of approximately 30-100 nM. In vitro kinase profiling revealed that 7x is a multikinase inhibitor with potent inhibitory activity against the CDK4/CYCLIN D1 and ARK5 kinases. Here, we report the synthesis, structure-activity relationship, kinase inhibitory profile, in vitro cytotoxicity, and in vivo tumor regression studies by this lead compound.

Original languageEnglish (US)
Pages (from-to)578-599
Number of pages22
JournalJournal of Medicinal Chemistry
Volume57
Issue number3
DOIs
StatePublished - Feb 13 2014
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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    Reddy, M. V. R., Akula, B., Cosenza, S. C., Athuluridivakar, S., Mallireddigari, M. R., Pallela, V. R., Billa, V. K., Subbaiah, D. R. C. V., Bharathi, E. V., Vasquez-Del Carpio, R., Padgaonkar, A., Baker, S. J., & Reddy, E. P. (2014). Discovery of 8-cyclopentyl-2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-7- oxo-7,8-dihydro-pyrido[2,3- d ]pyrimidine-6-carbonitrile (7x) as a potent inhibitor of cyclin-dependent kinase 4 (CDK4) and AMPK-related kinase 5 (ARK5). Journal of Medicinal Chemistry, 57(3), 578-599. https://doi.org/10.1021/jm401073p