ICEC0942, an Orally Bioavailable Selective Inhibitor of CDK7 for Cancer Treatment.
ICEC0942, an Orally Bioavailable Selective Inhibitor of CDK7 for Cancer Treatment.
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DOI：
10.1158/1535-7163.mct-16-0847
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发表时间：
2018-06
影响因子：
5.7
通讯作者：
Ali S
中科院分区：
文献类型：
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作者：
Patel H;Periyasamy M;Sava GP;Bondke A;Slafer BW;Kroll SHB;Barbazanges M;Starkey R;Ottaviani S;Harrod A;Aboagye EO;Buluwela L;Fuchter MJ;Barrett AGM;Coombes RC;Ali S
最近的报道表明，一些癌症类型对转录抑制特别敏感，这表明靶向转录机制为癌症治疗提供了新的方法。细胞周期蛋白依赖性激酶（CDK）7是转录所必需的，并且通过磷酸化RNA聚合酶II（PolII）的C末端结构域（CTD）来使转录启动。CDK 7还调节许多转录因子的活性，包括雌激素受体-α（ER）。在这里，我们描述了一种新型口服生物可利用的CDK 7抑制剂ICEC 0942。它选择性抑制CDK 7，IC 50为40 nM; CDK 1，CDK 2，CDK 5和CDK 9的IC 50值分别高出45，15，230和30倍。体外研究表明，多种癌症类型对CDK 7抑制敏感，GI 50值在0.2-0.3 µM之间。在乳腺癌和结直肠癌的异种移植物中，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完全生长停滞。我们的研究结果表明，CDK 7抑制提供了一种新的方法，特别是对于ER阳性乳腺癌，并确定ICEC 0942作为原型药物，具有作为单一药物或与乳腺癌激素治疗联合使用的潜在效用。ICEC 0942也可能对其他表现出转录因子成瘾特征的癌症有效，如急性白血病和小细胞肺癌。
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-α (ER). Here we describe a new, orally bioavailable CDK7 inhibitor, ICEC0942. It selectively inhibits CDK7, with an IC50 of 40nM; 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 0.2-0.3 µM. In xenografts of both breast and colorectal cancers, the drug has substantial anti-tumor effects. Additionally, 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.