title: Synthesis and evaluation of indenopyrazoles as cyclin-dependent kinase inhibitors. 2. Probing the indeno ring substituent pattern.
abstract: We disclose a novel series of indenopyrazole-based cyclin-dependent kinase (CDK) inhibitors. Kinetic experiments confirmed our initial molecular modeling studies that the compounds are competitive with respect to adenosine 5'-triphosphate (ATP) and bind in the kinase ATP pocket. A unique combination of active pharmacophores led us to a series of semicarbazide-based inhibitors that are highly potent against CDK2 and CDK4 while maintaining selectivity against other relevant serine/threonine kinases. These compounds were active against a transformed human colon cancer cell line (HCT116) while maintaining an acceptable margin of activity against a normal fibroblast cell line. The compounds were found to be highly protein bound in our cell-based assay with the exception of 11k, which maintained a reasonable level of activity in the presence of human plasma proteins.
authors.affiliation: Bristol-Myers Squibb Company, Box 80336, Wilmington, Delaware 19880-0336, USA. david.nugiel@bms.com
authors.forename: David A
authors.initials: DA
authors.lastname: Nugiel
authors.forename: Anup
authors.initials: A
authors.lastname: Vidwans
authors.forename: Anna-Marie
authors.initials: AM
authors.lastname: Etzkorn
authors.forename: Karen A
authors.initials: KA
authors.lastname: Rossi
authors.forename: Pamela A
authors.initials: PA
authors.lastname: Benfield
authors.forename: Catherine R
authors.initials: CR
authors.lastname: Burton
authors.forename: Sarah
authors.initials: S
authors.lastname: Cox
authors.forename: Deborah
authors.initials: D
authors.lastname: Doleniak
authors.forename: Steven P
authors.initials: SP
authors.lastname: Seitz
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000494:pharmacology / Q000633:toxicity; D001798:Blood Proteins / Q000378:metabolism; D042846:CDC2-CDC28 Kinases; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D051357:Cyclin-Dependent Kinase 2; D051358:Cyclin-Dependent Kinase 4; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors*; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology / Q000633:toxicity; D006801:Humans; D007700:Kinetics; D008958:Models, Molecular; D009025:Morpholines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D011518:Proto-Oncogene Proteins; D011720:Pyrazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology / Q000633:toxicity; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
chemical_list: C469560:3-(4-methoxyphenyl)-5-(morpholinylcarbamoyl)aminoindeno(1,2-c)pyrazol-4-one; D000970:Antineoplastic Agents; D001798:Blood Proteins; D004791:Enzyme Inhibitors; D009025:Morpholines; D011518:Proto-Oncogene Proteins; D011720:Pyrazoles; D017346:Protein Serine-Threonine Kinases; D042846:CDC2-CDC28 Kinases; C495894:CDK2 protein, human; C495900:CDK4 protein, human; D051357:Cyclin-Dependent Kinase 2; D051358:Cyclin-Dependent Kinase 4; D018844:Cyclin-Dependent Kinases