2. Academic Validation
  3. Pan-Transcriptional Enhanced Associated Domain Palmitoylation Pocket Covalent Inhibitor

Pan-Transcriptional Enhanced Associated Domain Palmitoylation Pocket Covalent Inhibitor

  • J Med Chem. 2024 Nov 14;67(21):18957-18968. doi: 10.1021/acs.jmedchem.4c01393.
Jinhyuk Kim 1 2,  Hadong Kim 2,  Jongwan Kim 3 4,  Seon Yeon Cho 2,  Sungho Moon 2,  Youngki Yoo 2,  Hanseong Kim 2,  Jin Kwan Kim 2,  Hyejin Jeon 5,  Wan Namkung 5,  Gyoonhee Han 6 5 7,  Kyoung Tai No 2 8
Affiliations

Affiliations

  • 1 The Interdisciplinary Graduate Program in Integrative Biotechnology & Translational Medicine, Yonsei University, Incheon 21983, Republic of Korea.
  • 2 Baobab AiBIO Co., Ltd., Incheon 21983, Republic of Korea.
  • 3 Bioinformatics and Molecular Design Research Center (BMDRC), Incheon 21983, Republic of Korea.
  • 4 Department of Structural Biology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, United States.
  • 5 Department of Pharmacy, Yonsei University, Incheon 21983, Republic of Korea.
  • 6 Department of Biotechnology, Yonsei University, Seoul 03722, Republic of Korea.
  • 7 Postech Biotech Center, 77 Cheongam-Ro, Nam-gu, Pohang, Gyeongbuk 37673, Korea.
  • 8 Institute of Convergence Science and Technology, Yonsei University, Incheon 21983, Republic of Korea.
PMID: 39487823 DOI: 10.1021/acs.jmedchem.4c01393
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.

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