Discovery of dioxo-benzo[b]thiophene derivatives as potent YAP-TEAD interaction inhibitors for treating breast cancer.

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 μM), endogenous target gene (e.g., CTGF and CYR61) expression, breast cancer cell growth (GI50 = 3.2 μM), and anchorage-independent growth in soft agar. Molecular docking analysis suggested 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.

• Authors: Youngchai Son, Jaeyeal Kim, Yongchan Kim, Sung-Gil Chi, Tackhoon Kim, Jinha Yu
• Journal: Bioorganic chemistry (Bioorg Chem) Vol. 131 Pg. 106274 (02 2023) ISSN: 1090-2120 [Electronic] United States
• PMID: 36434952 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2022 Elsevier Inc. All rights reserved.

Chemical References

• Transcription Factors
• Amides

Topics

• Humans
• Female
• Breast Neoplasms (drug therapy)
• Molecular Docking Simulation
• Transcription Factors (metabolism)
• Amides