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.
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.
Misra
Raj N
RN
Bristol-Myers Squibb Pharmaceutical Research Institute, PO Box 4000, Princeton, New Jersey 08543-4000, USA. raj_n_misra@hotmail.com
Xiao
Hai-yun
HY
Kim
Kyoung S
KS
Lu
Songfeng
S
Han
Wen-Ching
WC
Barbosa
Stephanie A
SA
Hunt
John T
JT
Rawlins
David B
DB
Shan
Weifang
W
Ahmed
Syed Z
SZ
Qian
Ligang
L
Chen
Bang-Chi
BC
Zhao
Rulin
R
Bednarz
Mark S
MS
Kellar
Kristen A
KA
Mulheron
Janet G
JG
Batorsky
Roberta
R
Roongta
Urvashi
U
Kamath
Amrita
A
Marathe
Punit
P
Ranadive
Sunanda A
SA
Sack
John S
JS
Tokarski
John S
JS
Pavletich
Nikola P
NP
Lee
Francis Y F
FY
Webster
Kevin R
KR
Kimball
S David
SD
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
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