2. Academic Validation
  3. Selective Degradation of TEADs by a PROTAC Molecule Exhibited Robust Anticancer Efficacy In Vitro and In Vivo

Selective Degradation of TEADs by a PROTAC Molecule Exhibited Robust Anticancer Efficacy In Vitro and In Vivo

  • J Med Chem. 2025 Jan 13. doi: 10.1021/acs.jmedchem.4c02884.
Yuhang Lu 1 2,  Ziqin Yan 1,  Jiaqi Sun 3 2,  Chenxu Wang 4,  Lan Xu 3,  Xilin Lyu 1,  Xiancheng Wang 1 2,  Jianfeng Lou 1 2,  He Huang 3 4 5,  Linghua Meng 3 2,  Yujun Zhao 6 1 2 4
Affiliations

Affiliations

  • 1 State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Rd, Shanghai 201203, China.
  • 2 University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing 100049, China.
  • 3 State Key Laboratory of Chemical Biology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
  • 4 School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing 210023, China.
  • 5 School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou 310024, China.
  • 6 Key Laboratory of Protection, Development and Utilization of Medicinal Resources in Liupanshan Area, Ministry of Education, School of Pharmacy, Ningxia Medical University, 1160 Shengli Street, Yinchuan, Ningxia Province 750004, China.
PMID: 39804031 DOI: 10.1021/acs.jmedchem.4c02884
Abstract

Genetic mutations in components of the Hippo pathway frequently lead to the aberrant activation of TEADs, which is often associated with Cancer. Consequently, TEADs have been actively pursued as therapeutic targets for diseases driven by TEAD overactivation. In this study, we report two series of TEAD PROTACs based on CRBN Binders and VHL Binders. Both series yielded potent TEAD degraders, including 19 and 40 (H122), which induced TEAD1 degradation with DC50 < 10 nM. Mechanistic studies demonstrated that the degradation of TEAD1 induced by 40 relied on CRBN binding, TEAD1 binding, E3 Ligase activity, and a functional Proteasome. RNA-seq analyses indicated that 40 significantly downregulated the expression of Myc target genes, as highlighted by GSEA analysis. More importantly, 40 exhibited robust antitumor efficacy in the MSTO-211H mouse xenograft model. Collectively, our results suggest that TEAD PROTACs have therapeutic potential for the treatment of cancers associated with TEAD overactivation.

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