title: N-(cycloalkylamino)acyl-2-aminothiazole inhibitors of cyclin-dependent kinase 2. N-[5-[[[5-(1,1-dimethylethyl)-2-oxazolyl]methyl]thio]-2-thiazolyl]-4- piperidinecarboxamide (BMS-387032), a highly efficacious and selective antitumor agent.
abstract: N-Acyl-2-aminothiazoles with nonaromatic acyl side chains containing a basic amine were found to be potent, selective inhibitors of CDK2/cycE which exhibit antitumor activity in mice. In particular, compound 21 [N-[5-[[[5-(1,1-dimethylethyl)-2-oxazolyl]methyl]thio]-2-thiazolyl]-4-piperidinecarboxamide, BMS-387032], has been identified as an ATP-competitive and CDK2-selective inhibitor which has been selected to enter Phase 1 human clinical trials as an antitumor agent. In a cell-free enzyme assay, 21 showed a CDK2/cycE IC(50) = 48 nM and was 10- and 20-fold selective over CDK1/cycB and CDK4/cycD, respectively. It was also highly selective over a panel of 12 unrelated kinases. Antiproliferative activity was established in an A2780 cellular cytotoxicity assay in which 21 showed an IC(50) = 95 nM. Metabolism and pharmacokinetic studies showed that 21 exhibited a plasma half-life of 5-7 h in three species and moderately low protein binding in both mouse (69%) and human (63%) serum. Dosed orally to mouse, rat, and dog, 21 showed 100%, 31%, and 28% bioavailability, respectively. As an antitumor agent in mice, 21 administered at its maximum-tolerated dose exhibited a clearly superior efficacy profile when compared to flavopiridol in both an ip/ip P388 murine tumor model and in a s.c./i.p. A2780 human ovarian carcinoma xenograft model.
authors.affiliation: Bristol-Myers Squibb Pharmaceutical Research Institute, PO Box 4000, Princeton, New Jersey 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: Kyoung S
authors.initials: KS
authors.lastname: Kim
authors.forename: Songfeng
authors.initials: S
authors.lastname: Lu
authors.forename: Wen-Ching
authors.initials: WC
authors.lastname: Han
authors.forename: Stephanie A
authors.initials: SA
authors.lastname: Barbosa
authors.forename: John T
authors.initials: JT
authors.lastname: Hunt
authors.forename: David B
authors.initials: DB
authors.lastname: Rawlins
authors.forename: Weifang
authors.initials: W
authors.lastname: Shan
authors.forename: Syed Z
authors.initials: SZ
authors.lastname: Ahmed
authors.forename: Ligang
authors.initials: L
authors.lastname: Qian
authors.forename: Bang-Chi
authors.initials: BC
authors.lastname: Chen
authors.forename: Rulin
authors.initials: R
authors.lastname: Zhao
authors.forename: Mark S
authors.initials: MS
authors.lastname: Bednarz
authors.forename: Kristen A
authors.initials: KA
authors.lastname: Kellar
authors.forename: Janet G
authors.initials: JG
authors.lastname: Mulheron
authors.forename: Roberta
authors.initials: R
authors.lastname: Batorsky
authors.forename: Urvashi
authors.initials: U
authors.lastname: Roongta
authors.forename: Amrita
authors.initials: A
authors.lastname: Kamath
authors.forename: Punit
authors.initials: P
authors.lastname: Marathe
authors.forename: Sunanda A
authors.initials: SA
authors.lastname: Ranadive
authors.forename: John S
authors.initials: JS
authors.lastname: Sack
authors.forename: John S
authors.initials: JS
authors.lastname: Tokarski
authors.forename: Nikola P
authors.initials: NP
authors.lastname: Pavletich
authors.forename: Francis Y F
authors.initials: FY
authors.lastname: Lee
authors.forename: Kevin R
authors.initials: KR
authors.lastname: Webster
authors.forename: S David
authors.initials: SD
authors.lastname: Kimball
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D042846:CDC2-CDC28 Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D045744:Cell Line, Tumor; D002474:Cell-Free System; D018360:Crystallography, X-Ray; D019927:Cyclin E / Q000378:metabolism; D051357:Cyclin-Dependent Kinase 2; D004285:Dogs; D004354:Drug Screening Assays, Antitumor; D004355:Drug Stability; D006801:Humans; D066298:In Vitro Techniques; D051379:Mice; D008862:Microsomes, Liver / Q000378:metabolism; D008958:Models, Molecular; D015394:Molecular Structure; D009368:Neoplasm Transplantation; D010080:Oxazoles / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D010766:Phosphorylation; D051381:Rats; D016160:Retinoblastoma Protein / Q000378:metabolism; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D014183:Transplantation, Heterologous
chemical_list: D000970:Antineoplastic Agents; D019927:Cyclin E; C484864:N-(5-(((5-(1,1-dimethylethyl)-2-oxazolyl)methyl)thio)-2-thiazolyl)-4-piperidinecarboxamide; D010080:Oxazoles; D016160:Retinoblastoma Protein; D013844:Thiazoles; D042846:CDC2-CDC28 Kinases; C495894:CDK2 protein, human; C495893:Cdk2 protein, mouse; C495892:Cdk2 protein, rat; D051357:Cyclin-Dependent Kinase 2