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).
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.affiliation: Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai , 1425 Madison Avenue, New York, New York 10029-6514, United States.
authors.forename: M V Ramana
authors.initials: MV
authors.lastname: Reddy
authors.forename: Balireddy
authors.initials: B
authors.lastname: Akula
authors.forename: Stephen C
authors.initials: SC
authors.lastname: Cosenza
authors.forename: Saikrishna
authors.initials: S
authors.lastname: Athuluridivakar
authors.forename: Muralidhar R
authors.initials: MR
authors.lastname: Mallireddigari
authors.forename: Venkat R
authors.initials: VR
authors.lastname: Pallela
authors.forename: Vinay K
authors.initials: VK
authors.lastname: Billa
authors.forename: D R C Venkata
authors.initials: DR
authors.lastname: Subbaiah
authors.forename: E Vijaya
authors.initials: EV
authors.lastname: Bharathi
authors.forename: Rodrigo
authors.initials: R
authors.lastname: Vasquez-Del Carpio
authors.forename: Amol
authors.initials: A
authors.lastname: Padgaonkar
authors.forename: Stacey J
authors.initials: SJ
authors.lastname: Baker
authors.forename: E Premkumar
authors.initials: EP
authors.lastname: Reddy
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D051358:Cyclin-Dependent Kinase 4 / Q000037:antagonists & inhibitors*; D004354:Drug Screening Assays, Antitumor; D005260:Female; D064593:Heterografts; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D062105:Molecular Docking Simulation; D009368:Neoplasm Transplantation; D011494:Protein Kinases; D011725:Pyridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D012097:Repressor Proteins / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
chemical_list: C587718:8-cyclopentyl-2-(4-(4-methylpiperazin-1-yl)phenylamino)-7-oxo-7,8-dihydropyrido(2,3-d)pyrimidine-6-carbonitrile; D000970:Antineoplastic Agents; D011725:Pyridines; D011743:Pyrimidines; D012097:Repressor Proteins; D011494:Protein Kinases; C470845:NUAK1 protein, human; D051358:Cyclin-Dependent Kinase 4