三阴性乳腺癌
癌症研究
癌细胞
乳腺癌
化学
转移
细胞周期蛋白
癌症
细胞周期蛋白依赖激酶
生物
细胞
细胞周期
生物化学
遗传学
作者
Shasha Cheng,Guan‐Jun Yang,Wanhe Wang,Dik‐Lung Ma,Chung‐Hang Leung
标识
DOI:10.1016/j.gendis.2021.06.005
摘要
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.
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