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

被引：2

作者：

Zhang, Limei ^{[1
,2
,3
]}

Wu, Lihong ^{[1
,2
,3
]}

Zhou, Duanfang ^{[1
,2
,3
]}

Wang, Gang ^{[1
,2
,3
]}

Chen, Bo ^{[1
,2
,3
]}

Shen, Zhengze ^{[5
]}

Li, Xiaoli ^{[1
,2
,3
]}

Wu, Qiuya ^{[1
,2
,3
]}

Qu, Na ^{[1
,2
,3
]}

Wu, Yuanli ^{[1
,2
,3
]}

Yuan, Lie ^{[1
,2
,3
]}

Gan, Zongjie ^{[4
]}

Zhou, Weiying ^{[1
,2
,3
]}

机构：

[1] Chongqing Med Univ, Coll Pharm, Dept Pharmacol, Chongqing 400016, Peoples R China

[2] Chongqing Key Lab Drug Metab, Chongqing 400016, Peoples R China

[3] Key Lab Biochem & Mol Pharmacol Chongqing, Chongqing 400016, Peoples R China

[4] Chongqing Med Univ, Coll Pharm, Dept Med Chem, Chongqing 400016, Peoples R China

[5] Chongqing Med Univ, Dept Pharm, Yongchuan Hosp, 439 Xuanhua Rd, Chongqing 402160, Peoples R China

来源：

EUROPEAN JOURNAL OF PHARMACOLOGY | 2023年 / 955卷

基金：

中国国家自然科学基金;

关键词：

Triple negative breast cancer; Cyclin dependent kinase 7; N76-1; Cell cycle; Apoptosis; PHOSPHORYLATION; TRANSCRIPTION; APOPTOSIS; THERAPY; GADD45G;

D O I：

10.1016/j.ejphar.2023.175892

中图分类号：

R9 [药学];

学科分类号：

1007 ;

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.

引用

页数：11

共 44 条

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