2. Academic Validation
  3. Discovery of a Potent and Selective TEAD Degrader with Durable Degradation Activity

Discovery of a Potent and Selective TEAD Degrader with Durable Degradation Activity

  • Adv Sci (Weinh). 2025 Oct 5:e03277. doi: 10.1002/advs.202503277.
Linhui Cao 1 2,  Jing Yang 3,  Yuhang Liu 1 2,  Xiaotong Chen 3,  Yufang Shi 4,  Yunshuo Zhao 3,  Yong Zhang 4,  Jian Chen 4,  Bowen Li 3,  Wuqiang Wen 5,  Lu Chen 2,  Bo Peng 2,  Lu Huang 2 6,  Yanli Sun 2,  Lixin Zhou 2 3,  Matthew G Rees 7,  Melissa M Ronan 7,  Jennifer A Roth 7,  Zhixiang Guo 6,  Jing Xing 2,  Guangya Zhu 2,  Yazhou Wang 4,  Baishan Jiang 5,  Jing Lu 1,  Kehao Zhao 1 4,  Wenchao Lu 2
Affiliations

Affiliations

  • 1 School of Pharmacy, Key Laboratory of Molecular Pharmacology and Drug Evaluation (Yantai University), Ministry of Education, China, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Yantai University, Yantai, 264005, China.
  • 2 Lingang Laboratory, Shanghai, 200031, China.
  • 3 Department of Hematology, Tongji Hospital, Frontier Science Center for Stem Cell Research, Shanghai Key Laboratory of Signaling and Disease Research, School of Life Sciences and Technology, Tongji University, Shanghai, 200092, China.
  • 4 Kygent Therapeutics, Shanghai, 201203, China.
  • 5 Department of Radiation and Medical Oncology, Medical Research Institute, Frontier Science Center of Immunology and Metabolism, Zhongnan Hospital of Wuhan University, School of Pharmaceutical Sciences, Wuhan University, Wuhan, 430071, China.
  • 6 Department of Cardiovascular Surgery, The First Affiliated Hospital of Anhui Medical University, 218 Jixi Road, Hefei, 230022, China.
  • 7 Broad Institute of MIT and Harvard, Cambridge, Massachusetts, 02142, USA.
PMID: 41047480 DOI: 10.1002/advs.202503277
Abstract

The TEA/ATSS (TEAD) family of transcription factors are key effectors of the Hippo pathway, exerting their function through interactions with the coactivators YAP and TAZ. Over the past five years, the development of YAP-TEAD disruptors has emerged as a central focus of both academic and industrial efforts aimed at targeting the Hippo pathway for Cancer therapy. In this study, the discovery and comprehensive characterization of KG-FP-003, a potent, selective, and durable TEAD degrader is reported. KG-FP-003 exhibits superior activity compared to the lipid-binding pocket (LBP) inhibitor MYF-03-176 and the TEAD-YAP protein-protein interaction (PPI) inhibitor IAG933, efficiently degrading all TEAD isoforms at low nanomolar concentrations in a ubiquitin-proteasome system (UPS)-dependent manner. This degradation translates into more robust and sustained therapeutic responses both in vitro and in vivo. Furthermore, barcoded cell line screening revealed elevated sensitivity in several Cancer types, including endometrial carcinoma, glioblastoma, ovarian epithelial tumors, and osteosarcoma. These findings position KG-FP-003 as a compelling lead candidate for TEAD isoform-selective therapies and underscore its potential utility beyond Hippo-dysregulated mesothelioma.

Keywords

TEAD; YAP; chemical probe; degrader; hippo pathway.

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