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*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

3 Citations (Scopus)

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.

Original languageEnglish
Number of pages15
JournalGenes and Diseases
DOIs
Publication statusE-pub ahead of print - 10 Jul 2021

Scopus Subject Areas

  • Biochemistry
  • Molecular Biology
  • Genetics(clinical)
  • Cell Biology

User-Defined Keywords

  • Cancer stem cells
  • CDK9-cyclin T1
  • Epithelial mesenchymal transition
  • Protein–protein interaction (PPI)
  • Triple-negative breast cancer (TNBC)

Fingerprint

Dive into the research topics of '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'. Together they form a unique fingerprint.

Cite this