Misra Raj N, Xiao Hai-yun, Kim Kyoung S, Lu Songfeng, Han Wen-Ching, Barbosa Stephanie A, Hunt John T, Rawlins David B, Shan Weifang, Ahmed Syed Z, Qian Ligang, Chen Bang-Chi, Zhao Rulin, Bednarz Mark S, Kellar Kristen A, Mulheron Janet G, Batorsky Roberta, Roongta Urvashi, Kamath Amrita, Marathe Punit, Ranadive Sunanda A, Sack John S, Tokarski John S, Pavletich Nikola P, Lee Francis Y F, Webster Kevin R, Kimball S David
Bristol-Myers Squibb Pharmaceutical Research Institute, PO Box 4000, Princeton, New Jersey 08543-4000, USA.
J Med Chem. 2004 Mar 25;47(7):1719-28. doi: 10.1021/jm0305568.
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.
发现带有含碱性胺的非芳香酰基侧链的N-酰基-2-氨基噻唑是有效的、选择性的CDK2/cycE抑制剂，在小鼠中表现出抗肿瘤活性。特别地，化合物21 [N-[5-[[[5-(1,1-二甲基乙基)-2-恶唑基]甲基]硫代]-2-噻唑基]-4-哌啶甲酰胺，BMS-387032]，已被鉴定为一种ATP竞争性和CDK2选择性抑制剂，已被选作抗肿瘤药物进入1期人体临床试验。在无细胞酶测定中，21显示CDK2/cycE的IC(50)=48 nM，对CDK1/cycB和CDK4/cycD的选择性分别为10倍和20倍。它对一组12种不相关激酶也具有高度选择性。在A2780细胞毒性测定中确定了抗增殖活性，其中21显示IC(50)=95 nM。代谢和药代动力学研究表明，21在三种物种中的血浆半衰期为5-7小时，在小鼠（69%）和人（63%）血清中的蛋白结合率均中等偏低。口服给予小鼠、大鼠和狗时，21的生物利用度分别为100%、31%和28%。作为小鼠中的抗肿瘤药物，在ip/ip P388小鼠肿瘤模型和s.c./i.p. A2780人卵巢癌异种移植模型中，与黄酮哌啶醇相比，以最大耐受剂量给药的21表现出明显更优的疗效。
