Development of highly potent and selective diaminothiazole inhibitors of cyclin-dependent kinases.
Development of highly potent and selective diaminothiazole inhibitors of cyclin-dependent kinases.
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DOI：
10.1021/jm301234k
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发表时间：
2013-05-23
影响因子：
7.3
通讯作者：
Georg, Gunda I.
中科院分区：
文献类型：
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作者：
Schonbrunn, Ernst;Betzi, Stephane;Alam, Riazul;Martin, Mathew P.;Becker, Andreas;Han, Huijong;Francis, Rawle;Chakrasali, Ramappa;Jakkaraj, Sudhakar;Kazi, Aslamuzzaman;Sebti, Said M.;Cubitt, Christopher L.;Gebhard, Anthony W.;Hazlehurst, Lori A.;Tash, Joseph S.;Georg, Gunda I.
细胞周期蛋白依赖性激酶（CDKs）是丝氨酸/苏氨酸蛋白激酶，在细胞周期进程中起关键调节作用。我们描述了通过高通量筛选发现的具有弱抑制活性（IC50 = 15µM）的单命中化合物（IC50 = 0.0009 - 0.0015µM）的高效CDK2二氨基噻唑抑制剂的开发（IC50 = 0.0009 - 0.0015µM）。利用CDK2的35个共晶结构与不同的母体化合物类似物配位，进行了基于结构的设计。化合物51对一组339种激酶的分析显示了对CDKs的高选择性，对CDK2和CDK5的选择性优于CDK9、CDK1、CDK4和CDK6。化合物51对15株肿瘤细胞株中13株的增殖有抑制作用，IC50值在0.27 ~ 6.9µM之间，这与完全抑制视网膜母细胞瘤磷酸化和细胞凋亡的发生有关。综上所述，这些结果表明了这种新的抑制剂系列进一步发展成为cdk特异性化学探针或治疗药物的潜力。
Cyclin-dependent kinases (CDKs) are serine/threonine protein kinases that act as key regulatory elements in cell cycle progression. We describe the development of highly potent diaminothiazole inhibitors of CDK2 (IC50 = 0.0009 – 0.0015 µM) from a single hit compound with weak inhibitory activity (IC50 = 15 µM), discovered by high-throughput screening. Structure-based design was performed using 35 co-crystal structures of CDK2 liganded with distinct analogues of the parent compound. The profiling of compound 51 against a panel of 339 kinases revealed high selectivity for CDKs, with preference for CDK2 and CDK5 over CDK9, CDK1, CDK4 and CDK6. Compound 51 inhibited the proliferation of 13 out of 15 cancer cell lines with IC50 values between 0.27 and 6.9 µM, which correlated with the complete suppression of retinoblastoma phosphorylation and the onset of apoptosis. Combined, the results demonstrate the potential of this new inhibitors series for further development into CDK-specific chemical probes or therapeutics.
影响因子：
46.9
作者：
通讯作者：
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影响因子：
2.9
作者：
ADAMS, JA;MCGLONE, ML;TAYLOR, SS
通讯作者：
TAYLOR, SS
影响因子：
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作者：
Ahn, JS;Radhakrishnan, ML;Kosik, KS
通讯作者：
Kosik, KS