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.

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 re

SUBMITTER: Cheng S 

PROVIDER: S-EPMC9485199 | biostudies-literature | 2022 Nov

REPOSITORIES: biostudies-literature