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-(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
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DOI：
10.1021/jm0305568
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发表时间：
2004-03-25
影响因子：
7.3
通讯作者：
Kimball, SD
中科院分区：
文献类型：
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作者：
Misra, RN;Xiao, HY;Kimball, SD
含有碱性胺的非芳香族酰基侧链的N-酰基-2-氨基噻唑被发现是在小鼠体内表现出抗肿瘤活性的CDK2/CycE的有效、选择性的抑制剂。特别是化合物21{N-[5-[[[5-(1，1-dimethylethyl)-2-oxazolyl]methyl]thio]-2-thiazolyl]-4-piperidinecarboxamide，BMS-387032}，已被确定为一种三磷酸腺苷竞争性和CDK2选择性的抑制剂，已被选为一期人类临床试验的抗肿瘤药物。在无细胞酶实验中，21的CDK2/CycE IC50=48 nM，比CDK1/CycB和CDK4/CyCD分别选择性高10倍和20倍。它对12个不相关的激酶也有很高的选择性。在A2780细胞毒性试验中，21例显示IC50=95 nM，证明了其抗增殖活性。代谢和药代动力学研究表明，21在三个物种中的血浆半衰期为5-7h，在小鼠(69%)和人(63%)血清中的蛋白结合率均为中等低。给小鼠、大鼠和狗口服，21的生物利用度分别为100%、31%和28%。作为一种小鼠抗肿瘤药物，在IP/IP P388小鼠肿瘤模型和sc/IP A2780人卵巢癌异种移植模型中，21在其最大耐受量给药后显示出明显优于黄吡哆醇的疗效。
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 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 IC50 = 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.