2. Academic Validation
  3. N76-1, a novel CDK7 inhibitor, exhibits potent anti-cancer effects in triple negative breast cancer

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

  • Eur J Pharmacol. 2023 Jul 8;175892. doi: 10.1016/j.ejphar.2023.175892.
Limei Zhang 1,  Lihong Wu 1,  Duanfang Zhou 1,  Gang Wang 1,  Bo Chen 1,  Zhengze Shen 2,  Xiaoli Li 1,  Qiuya Wu 1,  Na Qu 1,  Yuanli Wu 1,  Lie Yuan 1,  Zongjie Gan 3,  Weiying Zhou 4
Affiliations

Affiliations

  • 1 Department of Pharmacology, College of Pharmacy, Chongqing Medical University, Chongqing, 400016, China; Chongqing Key Laboratory of Drug Metabolism, Chongqing, 400016, China; Key Laboratory for Biochemistry and Molecular Pharmacology of Chongqing, Chongqing, 400016, China.
  • 2 Department of Pharmacy, Yongchuan Hospital of Chongqing Medical University, 439 Xuanhua Road, Yongchuan District, Chongqing, 402160, China.
  • 3 Department of Medicinal Chemistry, College of Pharmacy, Chongqing Medical University, Chongqing, 400016, China. Electronic address: gzj@cqmu.edu.cn.
  • 4 Department of Pharmacology, College of Pharmacy, Chongqing Medical University, Chongqing, 400016, China; Chongqing Key Laboratory of Drug Metabolism, Chongqing, 400016, China; Key Laboratory for Biochemistry and Molecular Pharmacology of Chongqing, Chongqing, 400016, China. Electronic address: wyzhou0118@163.com.
PMID: 37429520 DOI: 10.1016/j.ejphar.2023.175892
Abstract

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 Inhibitor 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 regulation 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.

Keywords

Apoptosis; Cell cycle; Cyclin dependent kinase 7; N76-1; Triple negative breast cancer.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-80013
    99.84%, CDK7 抑制剂
    CDK
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