Recent reports indicate that some cancer types are especially sensitive to transcription inhibition, suggesting that targeting the transcriptional machinery provides new approaches to cancer treatment. Cyclin-dependent kinase (CDK)7 is necessary for transcription, and acts by phosphorylating the C-terminal domain (CTD) of RNA polymerase II (PolII) to enable transcription initiation. CDK7 additionally regulates the activities of a number of transcription factors, including estrogen receptor (ER)-α. Here we describe a new, orally bioavailable CDK7 inhibitor, ICEC0942. It selectively inhibits CDK7, with an IC50 of 40 nmol/L; IC50 values for CDK1, CDK2, CDK5, and CDK9 were 45-, 15-, 230-, and 30-fold higher. In vitro studies show that a wide range of cancer types are sensitive to CDK7 inhibition with GI50 values ranging between 0.2 and 0.3 μmol/L. In xenografts of both breast and colorectal cancers, the drug has substantial antitumor effects. In addition, combination therapy with tamoxifen showed complete growth arrest of ER-positive tumor xenografts. Our findings reveal that CDK7 inhibition provides a new approach, especially for ER-positive breast cancer and identify ICEC0942 as a prototype drug with potential utility as a single agent or in combination with hormone therapies for breast cancer. ICEC0942 may also be effective in other cancers that display characteristics of transcription factor addiction, such as acute leukaemia and small-cell lung cancer. Mol Cancer Ther; 17(6); 1156–66. ©2018 AACR.

中文翻译：

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ICEC0942，一种口服生物可利用的 CDK7 选择性抑制剂，用于癌症治疗


最近的报告表明，某些癌症类型对转录抑制特别敏感，这表明针对转录机制为癌症治疗提供了新方法。细胞周期蛋白依赖性激酶 (CDK)7 是转录所必需的，它通过磷酸化 RNA 聚合酶 II (PolII) 的 C 末端结构域 (CTD) 来启动转录起始。 CDK7 还调节许多转录因子的活性，包括雌激素受体 (ER)-α。在这里，我们描述了一种新型口服生物可利用的 CDK7 抑制剂 ICEC0942。选择性抑制CDK7，IC50为40 nmol/L； CDK1、CDK2、CDK5 和 CDK9 的 IC50 值分别高出 45、15、230 和 30 倍。体外研究表明，多种癌症类型对 CDK7 抑制敏感，GI50 值范围在 0.2 至 0.3 μmol/L 之间。在乳腺癌和结直肠癌的异种移植中，该药物具有显着的抗肿瘤作用。此外，与他莫昔芬的联合治疗显示ER阳性肿瘤异种移植物的生长完全停滞。我们的研究结果表明，CDK7 抑制提供了一种新方法，特别是对于 ER 阳性乳腺癌，并将 ICEC0942 确定为原型药物，具有作为单一药物或与乳腺癌激素疗法联合使用的潜在用途。 ICEC0942也可能对其他表现出转录因子成瘾特征的癌症有效，例如急性白血病和小细胞肺癌。摩尔癌症治疗； 17(6)； 1156–66。 ©2018 AACR。