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

文献类型：期刊论文

作者Li, Huajie4,5,6; Ge, Zhiming3,4,6; Lin, Kexin2,3; He, Wei1,3; Chu, Qinyu3,4,6; Zheng, Mingyue1,2,3,4,6; Zhang, Sulin3,4; Xu, Tianfeng4,5,6
刊名ACS MEDICINAL CHEMISTRY LETTERS
出版日期2024-04-22
卷号15期号:5页码:631-639
关键词Hippo pathway TEAD PROTAC Selectivity
ISSN号1948-5875
DOI10.1021/acsmedchemlett.4c00029
通讯作者Zheng, Mingyue(myzheng@simm.ac.cn) ; Zhang, Sulin(slzhang@simm.ac.cn) ; Xu, Tianfeng(tfxu@simm.ac.cn)
英文摘要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.
WOS关键词HIPPO PATHWAY ; PALMITOYLATION ; GROWTH
资助项目National Natural Science Foundation of China[22107110] ; National Natural Science Foundation of China[T2225002] ; National Natural Science Foundation of China[2023296] ; Youth Innovation Promotion Association CAS
WOS研究方向Pharmacology & Pharmacy
语种英语
WOS记录号WOS:001226302400001
出版者AMER CHEMICAL SOC
源URL[http://119.78.100.183/handle/2S10ELR8/311108]  
专题新药研究国家重点实验室
通讯作者Zheng, Mingyue; Zhang, Sulin; Xu, Tianfeng
作者单位1.Nanchang Univ, Nanchang 330031, 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, Drug Discovery & Design Ctr, State Key Lab Drug Res, Shanghai 201203, Peoples R China
4.Univ Chinese Acad Sci, Beijing 100049, Peoples R China
5.Chinese Acad Sci, Shanghai Inst Mat Med, Dept Med Chem, Shanghai 201203, Peoples R China
6.Univ Chinese Acad Sci, Hangzhou Inst Adv Study, Sch Pharmaceut Sci & Technol, Hangzhou 310024, Peoples R China
推荐引用方式
GB/T 7714		 Li, Huajie,Ge, Zhiming,Lin, Kexin,et al. Design, Synthesis, and Bioevaluation of Transcriptional Enhanced Assocciated Domain (TEAD) PROTAC Degraders[J]. ACS MEDICINAL CHEMISTRY LETTERS,2024,15(5):631-639.
APA Li, Huajie.,Ge, Zhiming.,Lin, Kexin.,He, Wei.,Chu, Qinyu.,...&Xu, Tianfeng.(2024).Design, Synthesis, and Bioevaluation of Transcriptional Enhanced Assocciated Domain (TEAD) PROTAC Degraders.ACS MEDICINAL CHEMISTRY LETTERS,15(5),631-639.
MLA Li, Huajie,et al."Design, Synthesis, and Bioevaluation of Transcriptional Enhanced Assocciated Domain (TEAD) PROTAC Degraders".ACS MEDICINAL CHEMISTRY LETTERS 15.5(2024):631-639.

入库方式： OAI收割

来源：上海药物研究所

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