Discovery of a tetrahydroisoquinoline-based CDK9-cyclin T1 protein–protein interaction inhibitor as an anti-proliferative and anti-migration agent against triple-negative breast cancer cells

Shasha Cheng; Guan-Jun Yang; Wanhe Wang; Dik-Lung Ma; Chung-Hang Leung

doi:10.1016/j.gendis.2021.06.005

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Discovery of a tetrahydroisoquinoline-based CDK9-cyclin T1 protein–protein interaction inhibitor as an anti-proliferative and anti-migration agent against triple-negative breast cancer cells

更新时间：2022-11-09

- Discovery of a tetrahydroisoquinoline-based CDK9-cyclin T1 protein–protein interaction inhibitor as an anti-proliferative and anti-migration agent against triple-negative breast cancer cells
- Genes & Diseases Vol. 9, Issue 6, (2022)
- 作者机构：
  
  1. State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Taipa,Macao SAR,PR China
  2. Department of Chemistry, Hong Kong Baptist University, Kowloon Tong,Hong Kong SAR,PR China
  3. Institute of Medical Research, Northwestern Polytechnical University,Shaanxi,Xi'an,PR China,710072
  4. Department of Biomedical Sciences, Faculty of Health Sciences, University of Macau,Macao SAR,PR China
- 作者简介：
- 基金信息：
- DOI：10.1016/j.gendis.2021.06.005
  CLC：
- Published：2022，
  
  Published Online：1 November 2022，
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Shasha Cheng, Guan-Jun Yang, Wanhe Wang, et al. Discovery of a tetrahydroisoquinoline-based CDK9-cyclin T1 protein–protein interaction inhibitor as an anti-proliferative and anti-migration agent against triple-negative breast cancer cells. [J]. Genes & Diseases 9(6).(2022)
DOI：

Shasha Cheng, Guan-Jun Yang, Wanhe Wang, et al. Discovery of a tetrahydroisoquinoline-based CDK9-cyclin T1 protein–protein interaction inhibitor as an anti-proliferative and anti-migration agent against triple-negative breast cancer cells. [J]. Genes & Diseases 9(6).(2022) DOI： 10.1016/j.gendis.2021.06.005.

摘要

Abstract

Triple-negative breast cancer (TNBC) is a highly aggressive and metastasizing cancer that has the worst prognosis out of all breast cancer subtypes. The epithelial–mesenchymal transition (EMT) and cancer stem cells (CSCs) have been proposed as important mechanisms underlying TNBC metastasis. CDK9 is highly expressed in breast cancer

including TNBC

where it promotes EMT and induces cancer cell stemness. In this study

we have identified a tetrahydroisoquinoline derivative (compound 1) as a potent and selective CDK9-cyclin T1 inhibitor via virtual screening. Interestingly

by targeting the ATP binding site

compound 1 not only inhibited CDK9 activity but also disrupted the CDK9-cyclin T1 protein–protein interaction (PPI). Mechanistically

compound 1 reversed EMT and reduced the ratio of CSCs by blocking the CDK9-cyclin T1 interaction

leading to reduced TNBC cell proliferation and migration. To date

compound 1 is the first reported tetrahydroisoquinoline-based CDK9-cyclin T1 ATP-competitive inhibitor that also interferes with the interaction between CDK9 and cyclin T1. Compound 1 may serve as a promising scaffold for developing more selective and potent anti-TNBC agents. Our work also provides insight into the role of the CDK9-cyclin T1 PPI on EMT and CSCs and highlights the feasibility and significance of targeting CDK9 for the treatment of TNBC.

关键词

Keywords

Cancer stem cellsCDK9-cyclin T1Epithelial mesenchymal transitionProtein–protein interaction (PPI)Triple-negative breast cancer (TNBC)

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