Inhibition of the CDK9–cyclin T1 protein–protein interaction as a new approach against triple-negative breast cancer

Sha Sha Cheng, Yuan Qing Qu, Jia Wu, Guan Jun Yang, Hao Liu, Wanhe Wang, Qi Huang, Feng Chen, Guodong Li, Chun Yuen Wong, Vincent Kam Wai Wong*, Dik Lung Ma, Chung Hang Leung

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

Cyclin-dependent kinase 9 (CDK9) activity is correlated with worse outcomes of triple-negative breast cancer (TNBC) patients. The heterodimer between CDK9 with cyclin T1 is essential for maintaining the active state of the kinase and targeting this protein–protein interaction (PPI) may offer promising avenues for selective CDK9 inhibition. Herein, we designed and generated a library of metal complexes bearing the 7-chloro-2-phenylquinoline CˆN ligand and tested their activity against the CDK9–cyclin T1 PPI. Complex 1 bound to CDK9 via an enthalpically-driven binding mode, leading to disruption of the CDK9–cyclin T1 interaction in vitro and in cellulo. Importantly, complex 1 showed promising anti-metastatic activity against TNBC allografts in mice and was comparably active compared to cisplatin. To our knowledge, 1 is the first CDK9–cyclin T1 PPI inhibitor with anti-metastatic activity against TNBC. Complex 1 could serve as a new platform for the future design of more efficacious kinase inhibitors against cancer, including TNBC.

Original languageEnglish
Pages (from-to)1390-1405
Number of pages16
JournalActa Pharmaceutica Sinica B
Volume12
Issue number3
Early online date30 Oct 2021
DOIs
Publication statusPublished - Mar 2022

Scopus Subject Areas

  • Pharmacology, Toxicology and Pharmaceutics(all)

User-Defined Keywords

  • Epigenetics
  • Kinase inhibitor
  • Metal complex
  • Metastasis
  • Protein–protein interaction
  • Triple-negative breast cancer

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