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: Raj N Misra, Hai-yun Xiao, Kyoung S Kim, Songfeng Lu, Wen-Ching Han, Stephanie A Barbosa, John T Hunt, David B Rawlins, Weifang Shan, Syed Z Ahmed, Ligang Qian, Bang-Chi Chen, Rulin Zhao, Mark S Bednarz, Kristen A Kellar, Janet G Mulheron, Roberta Batorsky, Urvashi Roongta, Amrita Kamath, Punit Marathe, Sunanda A Ranadive, John S Sack, John S Tokarski, Nikola P Pavletich, Francis Y F Lee, Kevin R Webster, S David Kimball
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 47 Issue 7 Pg. 1719-28 (Mar 25 2004) ISSN: 0022-2623 [Print] United States
• PMID: 15027863 (Publication Type: Journal Article)

Chemical References

• Antineoplastic Agents
• Cyclin E
• N-(5-(((5-(1,1-dimethylethyl)-2-oxazolyl)methyl)thio)-2-thiazolyl)-4-piperidinecarboxamide
• Oxazoles
• Retinoblastoma Protein
• Thiazoles
• CDC2-CDC28 Kinases
• CDK2 protein, human
• Cdk2 protein, mouse
• Cdk2 protein, rat
• Cyclin-Dependent Kinase 2

Topics

• Animals
• Antineoplastic Agents (chemical synthesis, pharmacokinetics, pharmacology)
• CDC2-CDC28 Kinases (antagonists & inhibitors, metabolism)
• Cell Line, Tumor
• Cell-Free System
• Crystallography, X-Ray
• Cyclin E (metabolism)
• Cyclin-Dependent Kinase 2
• Dogs
• Drug Screening Assays, Antitumor
• Drug Stability
• Humans
• In Vitro Techniques
• Mice
• Microsomes, Liver (metabolism)
• Models, Molecular
• Molecular Structure
• Neoplasm Transplantation
• Oxazoles (chemical synthesis, pharmacokinetics, pharmacology)
• Phosphorylation
• Rats
• Retinoblastoma Protein (metabolism)
• Structure-Activity Relationship
• Thiazoles (chemical synthesis, pharmacokinetics, pharmacology)
• Transplantation, Heterologous