Integrated Strategic Design and In Situ Click Chemistry Approach to Rapid Discovery of Novel Potent Covalent TEAD Inhibitors

  • J Med Chem. 2026 May 14;69(9):10905-10923. doi: 10.1021/acs.jmedchem.6c00104.
Yuhui Miao  1  2  3 ,  Dounan Xu  4 ,  Xu Yang  1 ,  Hanrui Sun  5 ,  Yipan Luo  4 ,  Xiaochen Liang  2 ,  Shuang Hu  1  2  3 ,  Xiao Lin  2  6 ,  Jing Gao  2 ,  Xiaolin Luo  4 ,  Yi Pan  5 ,  Huan Xiong  4 ,  Cheng Luo  2  3  4  7 ,  Shijie Chen  1  2
Affiliations
  • 1. Innovation Center for AI and Drug Discovery, School of Pharmacy, East China Normal University, Shanghai 200062, China.
  • 2. State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
  • 3. University of Chinese Academy of Sciences, Beijing 100049, China.
  • 4. Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zhongshan 528400, China.
  • 5. School of Life Science and Technology, China Pharmaceutical University, Nanjing 211198, China.
  • 6. Department of Liver Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China.
  • 7. Guizhou Medical University, Guiyang 550014, China.
PMID: 42085464 DOI: 10.1021/acs.jmedchem.6c00104
Abstract

Transcriptional enhanced associated domain (TEAD) proteins, activated by YAP/TAZ, are oncogenic drivers. While parallel synthesis has advanced lead discovery, most libraries are assembled randomly or in a scaffold-centric manner, which results in low efficiency for inhibitor discovery. In this study, we leveraged a strategy integrating structure-based design with CuAAC-enabled parallel synthesis to build a covalent, hydrophobic-fragment library. Combined with in situ screening, this approach rapidly identified hits at 8.33%, among which LC-TEAD01 emerged as a selective inhibitor showing a 17-fold preference for NF2-deficient NCI-H226 cells. Biochemical and structural studies confirmed covalent engagement of the conserved cysteine and occupancy of the hydrophobic channel, disrupting YAP-TEAD interaction and suppressing TEAD-dependent transcription. In vivo, LC-TEAD01 inhibited tumor growth in NF2-deficient xenografts. Collectively, this work integrates structure-based design with CuAAC-enabled parallel synthesis and in situ screening, enabling rapid discovery of TEAD inhibitors and offering a generalizable route for targets with structurally defined pockets.

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