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).

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.

• Authors: 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
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 57 Issue 3 Pg. 578-99 (Feb 13 2014) ISSN: 1520-4804 [Electronic] United States
• PMID: 24417566 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• 8-cyclopentyl-2-(4-(4-methylpiperazin-1-yl)phenylamino)-7-oxo-7,8-dihydropyrido(2,3-d)pyrimidine-6-carbonitrile
• Antineoplastic Agents
• Pyridines
• Pyrimidines
• Repressor Proteins
• Protein Kinases
• NUAK1 protein, human
• Cyclin-Dependent Kinase 4

Topics

• Animals
• Antineoplastic Agents (chemical synthesis, chemistry, pharmacology)
• Apoptosis (drug effects)
• Cell Cycle (drug effects)
• Cell Line, Tumor
• Cyclin-Dependent Kinase 4 (antagonists & inhibitors)
• Drug Screening Assays, Antitumor
• Female
• Heterografts
• Humans
• Mice
• Mice, Nude
• Molecular Docking Simulation
• Neoplasm Transplantation
• Protein Kinases
• Pyridines (chemical synthesis, chemistry, pharmacology)
• Pyrimidines (chemical synthesis, chemistry, pharmacology)
• Repressor Proteins (antagonists & inhibitors)
• Structure-Activity Relationship