2. Academic Validation
  3. Design, Synthesis, and Bioevaluation of Transcriptional Enhanced Assocciated Domain (TEAD) PROTAC Degraders

Design, Synthesis, and Bioevaluation of Transcriptional Enhanced Assocciated Domain (TEAD) PROTAC Degraders

  • ACS Med Chem Lett. 2024 Apr 22;15(5):631-639. doi: 10.1021/acsmedchemlett.4c00029.
Huajie Li 1 2 3,  Zhiming Ge 1 3 4,  Kexin Lin 5 4,  Wei He 6 4,  Qinyu Chu 1 3 4,  Mingyue Zheng 1 3 4 5 6,  Sulin Zhang 3 4,  Tianfeng Xu 1 2 3
Affiliations

Affiliations

  • 1 School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, 310024, China.
  • 2 Department of Medicinal Chemistry, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai, 201203, China.
  • 3 University of Chinese Academy of Sciences, Beijing, 100049, China.
  • 4 Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai, 201203, China.
  • 5 School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, 210023, China.
  • 6 Nanchang University, Nanchang, 330031, China.
PMID: 38746898 DOI: 10.1021/acsmedchemlett.4c00029
Abstract

Dysregulation of the Hippo pathway has been observed in various cancers. The transcription factor TEAD, together with its coactivators YAP/TAZ, plays a crucial role in regulating the transcriptional output of the Hippo pathway. Recently, extensive research has focused on small molecule inhibitors targeting TEAD, but studies on TEAD degraders are comparatively rare. In this study, we designed and synthesized a series of TEAD PROTACs by connecting a pan-TEAD inhibitor with the CRBN ligand thalidomide. A representative compound, 27, exhibited potent antiproliferative activity against NF2-deficient NCI-H226 cells. It dose-dependently induced TEAD degradation dependent on CRBN and Proteasome system and decreased key YAP target genes CYR61 and CTGF expressions in NCI-H226 cells. Further degradation selectivity studies revealed that 27 exhibited more potent activity against TEAD2 compared to those of the other three family members in Flag-TEADs transfected 293T cells. Therefore, 27 may serve as a valuable tool for advancing biological studies related to TEAD2.

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