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Discovery of dioxo-benzo[b]thiophene derivatives as potent YAP-TEAD interaction inhibitors for treating breast cancer
- Title
- Discovery of dioxo-benzo[b]thiophene derivatives as potent YAP-TEAD interaction inhibitors for treating breast cancer
- Authors
- Son, Youngchai; Kim, Jaeyeal; Kim, Yongchan; Chi, Sung -Gil; Kim, Tackhoon; Yu, Jinha
- Ewha Authors
- 유진하
- SCOPUS Author ID
- 유진하
- Issue Date
- 2023
- Journal Title
- BIOORGANIC CHEMISTRY
- ISSN
- 0045-2068
1090-2120
- Citation
- BIOORGANIC CHEMISTRY vol. 131
- Keywords
- YAP; TAZ-TEAD; Protein-protein interaction inhibitor; Anticancer; Dioxo-benzo[b]thiophene scaffold
- Publisher
- ACADEMIC PRESS INC ELSEVIER SCIENCE
- Indexed
- SCIE; SCOPUS
- Document Type
- Article
- Abstract
- Disruption of protein-protein interaction between transcriptional enhancer factor (TEA)-domain (TEAD; a transcription factor) and its co-activator Yes-associated protein (YAP)/ transcriptional co-activator with PDZ-binding motif (TAZ) is a potential therapeutic strategy against various types of solid tumors. Based on hit compound 8 and 9a, hydrazone derivatives with dioxo-benzo[d]isothiazole (9b-n) and oxime ester (10a-s) or amide derivatives (11a-r) with dioxo-benzo[b]thiophene were designed and synthesized as novel TEAD-YAP interaction inhibitors. Amide derivative 11q exhibited a higher potency in inhibiting TEAD-YAP reporter expression activity (IC50 = 12.7 mu M), endogenous target gene (e.g., CTGF and CYR61) expression, breast cancer cell growth (GI50 = 3.2 mu M), and anchorage-independent growth in soft agar. Molecular docking analysis sug-gested that the newly synthesized compounds bound to interface 2 of TEAD had lower docking scores compared to the compounds that bind to interface 3; moreover, they were predicted to overlap with YAP. Therefore, we identified 11q as an attractive therapeutic agent for treating solid tumors overexpressing YAP/TAZ.
- DOI
- 10.1016/j.bioorg.2022.106274
- Appears in Collections:
- 약학대학 > 약학과 > Journal papers
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