Pan-Transcriptional Enhanced Associated Domain Palmitoylation Pocket Covalent Inhibitor

Jinhyuk Kim, Hadong Kim, Jongwan Kim, Seon Yeon Cho, Sungho Moon, Youngki Yoo, Hanseong Kim, Jin Kwan Kim, Hyejin Jeon, Wan Namkung, Gyoonhee Han, Kyoung Tai No

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1 Citation (Scopus)

Abstract

In the Hippo signaling pathway, the palmitoylated transcriptional enhanced associated domain (TEAD) protein interacts with the coactivator Yes-associated protein/PDZ-binding motif, leading to transcriptional upregulation of oncogenes such as Ctgf and Cyr61. Consequently, targeting the palmitoylation sites of TEAD has emerged as a promising strategy for treating TEAD-dependent cancers. Compound 1 was identified using a structure-based drug design approach, leveraging the molecular insights gained from the known TEAD palmitoylation site inhibitor, K-975. Optimization of the initial hit compound resulted in the development of compound 3, a covalent pan-TEAD inhibitor characterized by high potency and oral bioavailability.

Original languageEnglish
Pages (from-to)18957-18968
Number of pages12
JournalJournal of Medicinal Chemistry
Volume67
Issue number21
DOIs
Publication statusPublished - 2024 Nov 14

Bibliographical note

Publisher Copyright:
© 2024 American Chemical Society.

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Drug Discovery

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