N-(Cycloalkylamino)acyl-2-aminothiazole Inhibitors of Cyclin-Dependent Kinase 2. N-5-5-(1,1-Dimethylethyl)-2-oxazolylmethylthio-2-thiazolyl-4- piperidinecarboxamide (BMS-387032), a Highly Efficacious and Selective Antitumor Agent

摘要

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-oxazolylmethylthio-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 IC50 = 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 sc/ip A2780 human ovarian carcinoma xenograft model.