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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
Cheng, Shasha1; Yang, Guan Jun1; Wang, Wanhe2,3; Ma, Dik Lung2; Leung, Chung Hang1,4
2021
Source PublicationGenes and Diseases
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.

KeywordCancer Stem Cells Cdk9-cyclin T1 Epithelial Mesenchymal Transition Protein–protein Interaction (Ppi) Triple-negative Breast Cancer (Tnbc)
DOI10.1016/j.gendis.2021.06.005
URLView the original
Language英語English
Scopus ID2-s2.0-85111615470
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Cited Times [WOS]:6   [WOS Record]     [Related Records in WOS]
Document TypeJournal article
CollectionUniversity of Macau
Affiliation1.State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Taipa, China
2.Department of Chemistry, Hong Kong Baptist University, Hong Kong SAR, Kowloon Tong, Hong Kong
3.Institute of Medical Research, Northwestern Polytechnical University, Xi'an, China
4.Department of Biomedical Sciences, Faculty of Health Sciences, University of Macau, Macao SAR, China
First Author AffilicationInstitute of Chinese Medical Sciences
Recommended Citation
GB/T 7714
Cheng, Shasha,Yang, Guan Jun,Wang, Wanhe,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 and Diseases,2021.
APA Cheng, Shasha,Yang, Guan Jun,Wang, Wanhe,Ma, Dik Lung,&Leung, Chung Hang.(2021).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 and Diseases.
MLA Cheng, Shasha,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".Genes and Diseases (2021).
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