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Ref Type Journal Article
PMID (24417566)
Authors Reddy MV, Akula B, Cosenza SC, Athuluridivakar S, Mallireddigari MR, Pallela VR, Billa VK, Subbaiah DR, Bharathi EV, Vasquez-Del Carpio R, Padgaonkar A, Baker SJ, Reddy EP
Title 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 Journal of medicinal chemistry
Vol 57
Issue 3
Date 2014 Feb 13
URL
Abstract Text 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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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
ON123300 ON123300 1 0
Drug Name Trade Name Synonyms Drug Classes Drug Description
ON123300 7X|ON-123300|ON 123300 CDK4 Inhibitor 12 ON123300 inhibits CDK4 and ARK5 (NUAK1), resulting in decreased downstream signaling and increased tumor cell death (PMID: 24417566, PMID: 26873845).
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
Unknown unknown Advanced Solid Tumor not applicable ON123300 Preclinical Actionable In a preclinical study ON123300 inhibited growth of a variety of human solid tumor cell lines in culture (PMID: 24417566). 24417566