• 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, and S David Kimball.
• Bristol-Myers Squibb Pharmaceutical Research Institute, PO Box 4000, Princeton, New Jersey 08543-4000, USA. raj_n_misra@hotmail.com
• J. Med. Chem. 2004 Mar 25; 47 (7): 1719-28.

AbstractN-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.

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