1. Academic Validation
  2. 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)

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)

  • J Med Chem. 2014 Feb 13;57(3):578-99. doi: 10.1021/jm401073p.
M V Ramana Reddy 1 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
Affiliations

Affiliation

  • 1 Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai , 1425 Madison Avenue, New York, New York 10029-6514, United States.
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.

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