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

Youngchai Son, Jaeyeal Kim, Yongchan Kim, Sung Gil Chi, Tackhoon Kim, Jinha Yu

Research output: Contribution to journalArticlepeer-review

1 Citation (Scopus)

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.

Original languageEnglish
Article number106274
JournalBioorganic Chemistry
Volume131
DOIs
Publication statusPublished - 2023 Feb

Bibliographical note

Funding Information:
We thank Dae-Sik Lim and Ingyun Lee (Korea Institute of Science and Technology) for providing the plasmids and technical assistance. This study was supported by the Ministry of Science and ICT (MSIT), National Research Foundation of Korea (NRF-2022R1C1C1004804 and Bio & Medical Technology Development Program NRF-2022M3E5F3080873 to J.Y, 2021R1A2C1093499 to T.K.), and the Korea Institute of Science and Technology Institutional Program (2E31624) to T.K.

Funding Information:
We thank Dae-Sik Lim and Ingyun Lee (Korea Institute of Science and Technology) for providing the plasmids and technical assistance. This study was supported by the Ministry of Science and ICT (MSIT), National Research Foundation of Korea (NRF-2022R1C1C1004804 and Bio & Medical Technology Development Program NRF-2022M3E5F3080873 to J.Y, 2021R1A2C1093499 to T.K.), and the Korea Institute of Science and Technology Institutional Program (2E31624) to T.K.

Publisher Copyright:
© 2022 Elsevier Inc.

Keywords

  • Anticancer
  • Dioxo-benzo[b]thiophene scaffold
  • Protein-protein interaction inhibitor
  • YAP/TAZ-TEAD

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Drug Discovery
  • Organic Chemistry

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