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
© 2021 Chongqing Medical University. Production and hosting by Elsevier B.V..
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.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2022 |
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| Erschienen: |
2022 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:9 |
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| Enthalten in: |
Genes & diseases - 9(2022), 6 vom: 27. Nov., Seite 1674-1688 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Cheng, Shasha [VerfasserIn] |
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| Links: |
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| Themen: |
CDK9-cyclin T1 |
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| Anmerkungen: |
Date Revised 28.09.2022 published: Electronic-eCollection Citation Status PubMed-not-MEDLINE |
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| doi: |
10.1016/j.gendis.2021.06.005 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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NLM346737400 |
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| 520 | |a 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 | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a CDK9-cyclin T1 | |
| 650 | 4 | |a Cancer stem cells | |
| 650 | 4 | |a Epithelial mesenchymal transition | |
| 650 | 4 | |a Protein–protein interaction (PPI) | |
| 650 | 4 | |a Triple-negative breast cancer (TNBC) | |
| 700 | 1 | |a Yang, Guan-Jun |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Wanhe |e verfasserin |4 aut | |
| 700 | 1 | |a Ma, Dik-Lung |e verfasserin |4 aut | |
| 700 | 1 | |a Leung, Chung-Hang |e verfasserin |4 aut | |
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