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

文献类型：期刊论文

作者Lu, Yuhang4,5; Yan, Ziqin5; Sun, Jiaqi3,4; Wang, Chenxu2; Xu, Lan3; Lyu, Xilin5; Wang, Xiancheng4,5; Lou, Jianfeng4,5; Huang, He1,2,3; Meng, Linghua3,4
刊名JOURNAL OF MEDICINAL CHEMISTRY
出版日期2025-01-13
页码25
ISSN号0022-2623
DOI10.1021/acs.jmedchem.4c02884
英文摘要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.
WOS关键词FLUORESCENCE POLARIZATION ASSAY ; HIPPO PATHWAY ; STRUCTURAL BASIS ; SIZE-CONTROL ; NF2 GENE ; YAP ; INHIBITOR ; GROWTH ; DESIGN ; DOMAIN
资助项目National Natural Science Foundation of China[82073682] ; National Natural Science Foundation of China[82273759] ; National Natural Science Foundation of China[22277125] ; National Natural Science Foundation of China[92253306] ; National Natural Science Foundation of China[22ZR1474500] ; Science and Technology Commission of Shanghai Municipality[SIMM0320231008] ; Science and Technology Commission of Shanghai Municipality[SKLDR-2024-KF-01] ; State Key Laboratory of Drug Research at the Shanghai Institute of Materia Medica ; State Key Laboratory of Chemical Biology[XDB1060000] ; Strategic Priority Research Program of the Chinese Academy of Sciences
WOS研究方向Pharmacology & Pharmacy
语种英语
WOS记录号WOS:001397196300001
出版者AMER CHEMICAL SOC
源URL[http://119.78.100.183/handle/2S10ELR8/315678]  
专题新药研究国家重点实验室
通讯作者Huang, He; Meng, Linghua; Zhao, Yujun
作者单位1.Univ Chinese Acad Sci, Hangzhou Inst Adv Study, Sch Pharmaceut Sci & Technol, Hangzhou 310024, Peoples R China
2.Nanjing Univ Chinese Med, Sch Chinese Mat Med, Nanjing 210023, Peoples R China
3.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Chem Biol, Shanghai 201203, Peoples R China
4.Univ Chinese Acad Sci, Beijing 100049, Peoples R China
5.Chinese Acad Sci, State Key Lab Drug Res, Shanghai Inst Mat Med, Shanghai 201203, Peoples R China
推荐引用方式
GB/T 7714		 Lu, Yuhang,Yan, Ziqin,Sun, Jiaqi,et al. Selective Degradation of TEADs by a PROTAC Molecule Exhibited Robust Anticancer Efficacy In Vitro and In Vivo[J]. JOURNAL OF MEDICINAL CHEMISTRY,2025:25.
APA Lu, Yuhang.,Yan, Ziqin.,Sun, Jiaqi.,Wang, Chenxu.,Xu, Lan.,...&Zhao, Yujun.(2025).Selective Degradation of TEADs by a PROTAC Molecule Exhibited Robust Anticancer Efficacy In Vitro and In Vivo.JOURNAL OF MEDICINAL CHEMISTRY,25.
MLA Lu, Yuhang,et al."Selective Degradation of TEADs by a PROTAC Molecule Exhibited Robust Anticancer Efficacy In Vitro and In Vivo".JOURNAL OF MEDICINAL CHEMISTRY (2025):25.

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来源：上海药物研究所

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