"N76-1, a novel CDK7 inhibitor, exhibits potent anti-cancer effects in triple negative breast cancer"

作者全名："Zhang, Limei; Wu, Lihong; Zhou, Duanfang; Wang, Gang; Chen, Bo; Shen, Zhengze; Li, Xiaoli; Wu, Qiuya; Qu, Na; Wu, Yuanli; Yuan, Lie; Gan, Zongjie; Zhou, Weiying"

作者地址："[Zhang, Limei; Wu, Lihong; Zhou, Duanfang; Wang, Gang; Chen, Bo; Li, Xiaoli; Wu, Qiuya; Qu, Na; Wu, Yuanli; Yuan, Lie; Zhou, Weiying] Chongqing Med Univ, Coll Pharm, Dept Pharmacol, Chongqing 400016, Peoples R China; [Zhang, Limei; Wu, Lihong; Zhou, Duanfang; Wang, Gang; Chen, Bo; Li, Xiaoli; Wu, Qiuya; Qu, Na; Wu, Yuanli; Yuan, Lie; Zhou, Weiying] Chongqing Key Lab Drug Metab, Chongqing 400016, Peoples R China; [Zhang, Limei; Wu, Lihong; Zhou, Duanfang; Wang, Gang; Chen, Bo; Li, Xiaoli; Wu, Qiuya; Qu, Na; Wu, Yuanli; Yuan, Lie; Zhou, Weiying] Key Lab Biochem & Mol Pharmacol Chongqing, Chongqing 400016, Peoples R China; [Gan, Zongjie] Chongqing Med Univ, Coll Pharm, Dept Med Chem, Chongqing 400016, Peoples R China; [Shen, Zhengze] Chongqing Med Univ, Dept Pharm, Yongchuan Hosp, 439 Xuanhua Rd, Chongqing 402160, Peoples R China"

通信作者："Zhou, WY (通讯作者)，Chongqing Med Univ, Coll Pharm, Dept Pharmacol, Chongqing 400016, Peoples R China.; Zhou, WY (通讯作者)，Chongqing Key Lab Drug Metab, Chongqing 400016, Peoples R China.; Zhou, WY (通讯作者)，Key Lab Biochem & Mol Pharmacol Chongqing, Chongqing 400016, Peoples R China.; Gan, ZJ (通讯作者)，Chongqing Med Univ, Coll Pharm, Dept Med Chem, Chongqing 400016, Peoples R China."

来源：EUROPEAN JOURNAL OF PHARMACOLOGY

ESI学科分类：PHARMACOLOGY & TOXICOLOGY

WOS号：WOS:001042709400001

JCR分区：Q1

影响因子：4.2

年份：2023

卷号：955

期号：　

开始页：　

结束页：　

文献类型：Article

关键词：Triple negative breast cancer; Cyclin dependent kinase 7; N76-1; Cell cycle; Apoptosis

摘要："Emerging evidence suggests that genetically highly specific triple-negative breast cancer (TNBC) possesses a relatively uniform transcriptional program that is abnormally dependent on cyclin-dependent kinase 7 (CDK7). In this study, we obtained an inhibitor of CDK7, N76-1, by attaching the side chain of the covalent CDK7 in-hibitor THZ1 to the core of the anaplastic lymphoma kinase inhibitor ceritinib. This study aimed to elucidate the role and underlying mechanism of N76-1 in TNBC and evaluate its potential value as an anti-TNBC drug. The results of 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and colony formation assays showed that N76-1 inhibited the viability of TNBC cells. Kinase activity and cellular thermal shift assays showed that N76-1 directly targeted CDK7. Flow cytometry results revealed that N76-1 induced apoptosis and cell cycle arrest in the G2/M phase. N76-1 also effectively inhibited the migration of TNBC cells by high-content detection. The RNA-seq analysis showed that the transcription of genes, especially those related to transcriptional regu-lation and cell cycle, was suppressed after N76-1 treatment. Moreover, N76-1 markedly inhibited the growth of TNBC xenografts and phosphorylation of RNAPII in tumor tissues. In summary, N76-1 exerts potent anticancer effects in TNBC by inhibiting CDK7 and provides a new strategy and research basis for the development of new drugs for TNBC."

基金机构：National Natural Science Foundation of China [81874100]; Innovation research group in Colleges and Universities Program of Chongqing Municipal Education Commission [CXQT20012]; CQMU Program for Youth Innovation in Future Medicine [W0067]; High-level Young Scientific and Technolog-ical Talent Cultivation Pro-gram of Chongqing Medical University

基金资助正文：Funding This project was supported by grants from the National Natural Science Foundation of China (No.81874100) ; Innovation research group in Colleges and Universities Program of Chongqing Municipal Education Commission (No. CXQT20012) ; CQMU Program for Youth Innovation in Future Medicine (W0067) ; High-level Young Scientific and Technolog-ical Talent Cultivation Pro-gram of Chongqing Medical University.