Antitumor effects of a covalent cyclin-dependent kinase 7 inhibitor in colorectal cancer

Although both antiepidermal growth factor receptor and vascular endothelial growth factor therapies have been shown to be effective against colorectal cancer (CRC), their beneficial effects are limited to a small proportion of patients and are not sustainable. Cyclin-dependent kinase 7 (CDK7) is an important regulator of the transcriptional machinery. Use of small-molecule inhibitors of the transcriptional machinery has shown promising selectivity for cancer cells and potent antiproliferative effects. In this study, the effects of a covalent CDK7 inhibitor THZ1 as a potent anti-CRC compound were evaluated in vitro and in vivo. THZ1 significantly inhibited cell growth and induced apoptosis of CRC cells in vitro. In addition, it also decreased xenograft tumor growth in vivo. RNA-Seq showed that THZ1 induced inhibition of a number of oncogenic transcripts. Taken together, our results indicate that pharmacological modulation of CDK7 kinase activity by THZ1 may represent a potential strategy in the treatment of CRC. * Jian Wang and Zhenyu Li contributed equally to the writing of this article. Correspondence to Zhenyu Lin, Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan 430022, China Tel/fax: +86 27 8587 1982; e-mail: whxhlzy@163.com Received July 7, 2018 Accepted December 28, 2018 Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

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