The development of a selective cyclin-dependent kinase inhibitor that shows antitumor activity.
The development of a selective cyclin-dependent kinase inhibitor that shows antitumor activity.
复制标题
DOI：
10.1158/0008-5472.can-09-0301
复制
发表时间：
2009-08-01
期刊：
影响因子：
11.2
通讯作者：
Coombes RC
中科院分区：
文献类型：
--
作者：
Ali S;Heathcote DA;Kroll SH;Jogalekar AS;Scheiper B;Patel H;Brackow J;Siwicka A;Fuchter MJ;Periyasamy M;Tolhurst RS;Kanneganti SK;Snyder JP;Liotta DC;Aboagye EO;Barrett AG;Coombes RC
细胞周期的正常进程需要细胞周期蛋白依赖性激酶CDK 1、CDK 2、CDK 4和CDK 6的顺序作用。CDK活性的直接或间接失调是几乎所有癌症的特征，并导致CDK抑制剂作为抗癌剂的发展。CDK-activating kinase（CAK）通过介导CDK 1、CDK 2、CDK 4和CDK 6的活化磷酸化而在细胞周期调控中起关键作用。因此，CDK 7也作为TFIIH基础转录因子的一部分调节转录，是开发抗癌药物的有吸引力的靶标。CDK 7结构的计算机建模用于设计潜在的有效CDK 7抑制剂。在这里，我们表明吡唑并[1，5-a]嘧啶衍生的化合物BS-181抑制CAK活性，IC 50 =21 nM。对其他CDK以及另外69种激酶的测试表明，BS-181仅在低于1 μM的浓度下抑制CDK 2，CDK 2的抑制效力比CDK 7低35倍（IC 50 =750 nM）。在MCF-7细胞中，BS-181可抑制CDK 7底物的磷酸化，促进细胞周期阻滞和凋亡，从而抑制癌细胞株的生长，在体内显示出抗肿瘤作用。该药物在体内稳定，以10 mg/kg腹腔给药后，小鼠的血浆消除半衰期为405 min。相同剂量的药物抑制MCF-7人裸鼠移植瘤的生长。因此，BS-181提供了具有作为抗癌剂潜力的有效和选择性CDK 7抑制剂的第一个实例。
Normal progression through the cell cycle requires the sequential action of cyclin-dependent kinases CDK1, CDK2, CDK4 and CDK6. Direct or indirect deregulation of CDK activity is a feature of almost all cancers, and has led to the development of CDK inhibitors as anti-cancer agents. The CDK-activating kinase (CAK) plays a critical role in regulating cell cycle by mediating the activating phosphorylation of CDK1, CDK2, CDK4 and CDK6. As such, CDK7, which also regulates transcription as part of the TFIIH basal transcription factor, is an attractive target for the development of anti-cancer drugs. Computer modelling of the CDK7 structure was used to design potential potent CDK7 inhibitors. Here, we show that a pyrazolo[1, 5–a]pyrimidine-derived compound, BS-181, inhibited CAK activity with an IC50=21 nM. Testing of other CDKs, as well as another 69 kinases showed that BS-181 only inhibited CDK2 at concentrations lower than 1 μM, with CDK2 being inhibited 35-fold less potently (IC50=750 nM) than CDK7. In MCF-7 cells, BS-181 inhibited the phosphorylation of CDK7 substrates, promoted cell cycle arrest and apoptosis, to inhibit the growth of cancer cell lines and showed anti-tumor effects in vivo. The drug was stable in vivo with a plasma elimination half-life in mice of 405 min after intraperitoneal administration of 10 mg/kg. The same dose of drug inhibited the growth of MCF-7 human xenografts in nude mice. BS-181 therefore provides the first example of a potent and selective CDK7 inhibitor with potential as an anti-cancer agent.