title: Synthesis and biological activity of N-aryl-2-aminothiazoles: potent pan inhibitors of cyclin-dependent kinases.
abstract: N-Aryl aminothiazoles 6-9 were prepared from 2-bromothiazole 5 and found to be CDK inhibitors. In cells they act as potent cytotoxic agents. Selectivity for CDK1, CDK2, and CDK4 was dependent of the nature of the N-aryl group and distinct from the CDK2 selective N-acyl analogues. The N-2-pyridyl analogues 7 and 19 showed pan CDK inhibitory activity. Elaborated analogues 19 and 23 exhibited anticancer activity in mice against P388 murine leukemia. The solid-state structure of 7 bound to CDK2 shows a similar binding mode to the N-acyl analogues.
authors.affiliation: Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, NJ 08543-4000, USA. raj_n_misra@hotmail.com
authors.forename: Raj N
authors.initials: RN
authors.lastname: Misra
authors.forename: Hai-yun
authors.initials: HY
authors.lastname: Xiao
authors.forename: David K
authors.initials: DK
authors.lastname: Williams
authors.forename: Kyoung S
authors.initials: KS
authors.lastname: Kim
authors.forename: Songfeng
authors.initials: S
authors.lastname: Lu
authors.forename: Kristen A
authors.initials: KA
authors.lastname: Keller
authors.forename: Janet G
authors.initials: JG
authors.lastname: Mulheron
authors.forename: Roberta
authors.initials: R
authors.lastname: Batorsky
authors.forename: John S
authors.initials: JS
authors.lastname: Tokarski
authors.forename: John S
authors.initials: JS
authors.lastname: Sack
authors.forename: S David
authors.initials: SD
authors.lastname: Kimball
authors.forename: Francis Y
authors.initials: FY
authors.lastname: Lee
authors.forename: Kevin R
authors.initials: KR
authors.lastname: Webster
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors*; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology; D020128:Inhibitory Concentration 50; D007938:Leukemia / Q000188:drug therapy; D051379:Mice; D009374:Neoplasms, Experimental / Q000188:drug therapy; D011485:Protein Binding; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000138:chemical synthesis / Q000494:pharmacology*; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D013844:Thiazoles; D018844:Cyclin-Dependent Kinases