Discovery and biological evaluation of carborane-containing derivatives as TEAD auto palmitoylation inhibitors

  • Bioorg Med Chem Lett. 2025 Jun 1:121:130155. doi: 10.1016/j.bmcl.2025.130155.
Chaofan Li  1 ,  Yingshuang Zhang  2 ,  Ziyin Zhang  2 ,  Yirong Zhang  1 ,  Yuxuan Song  2 ,  Linyuan Wang  1 ,  Changxian Yuan  1 ,  Guanxiang Hao  1 ,  Nan Sun  1 ,  Hongjing Li  1 ,  Zhiguang Zhang  3 ,  Yundong He  4 ,  Sinan Wang  5
Affiliations
  • 1. School of Biomedical Engineering & State Key Laboratory of Advanced Medical Materials and Devices, ShanghaiTech University, Shanghai 201210, China.
  • 2. Shanghai Key Laboratory of Regulatory Biology, The Institute of Biomedical Sciences, School of Life Sciences, East China Normal University, Shanghai, 200241, China.
  • 3. College of Chemical and Pharmaceutical Engineering, Hebei University of Science and Technology, Shijiazhuang 050018, China.
  • 4. Shanghai Key Laboratory of Regulatory Biology, The Institute of Biomedical Sciences, School of Life Sciences, East China Normal University, Shanghai, 200241, China. Electronic address: [email protected].
  • 5. School of Biomedical Engineering & State Key Laboratory of Advanced Medical Materials and Devices, ShanghaiTech University, Shanghai 201210, China. Electronic address: [email protected].
PMID: 40010443 DOI: 10.1016/j.bmcl.2025.130155
Abstract

Transcriptional enhanced associate domain (TEAD) proteins are key downstream effectors of the Hippo signaling pathway that play a crucial role in various cell processes including tissue development, regeneration, cell proliferation and Cancer. TEADs contain a hydrophobic auto-palmitoylation pocket that can bind palmitic acid and stabilize TEADs from being degraded. Inhibitors targeting this palmitoylation pocket typically consist of hydrophobic pharmacophores. Carboranes is a cage-shaped molecule exhibiting superior hydrophobicity compared to adamantane or phenyl groups. Herein, we incorporated carborane into known TEAD inhibitors for better interaction with the hydrophobic palmitate pocket. Compounds 1f and 1l are identified as TEAD transcription inhibitors with strong anti-proliferation and anti-migration activities toward prostate Cancer cell lines. They also significantly reduced TEAD-regulated downstream gene expressions.

Keywords
Anti-cancer activity; Carborane; Palmitoylation inhibitor; TEAD.
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