European Journal of Medicinal Chemistry (2019)
Update date:2022-08-16
Topics:
Lu, Wenchao
Wang, Jun
Li, Yong
Tao, Hongru
Xiong, Huan
Lian, Fulin
Gao, Jing
Ma, Hongna
Lu, Tian
Zhang, Dan
Ye, Xiaoqing
Ding, Hong
Yue, Liyan
Zhang, Yuanyuan
Tang, Huanyu
Zhang, Naixia
Yang, Yaxi
Jiang, Hualiang
Chen, Kaixian
Zhou, Bing
Luo, Cheng
Transcriptional enhancer associated domain family members (TEADs) are the most important downstream effectors that play the pivotal role in the development, regeneration and tissue homeostasis. Recent biochemical studies have demonstrated that TEADs could undergo autopalmitoylation that is indispensable for its function making the lipid-binding pocket an attractive target for chemical intervention. Herein, through structure-based virtual screen and rational medicinal chemistry optimization, we identified DC-TEADin02 as the most potent, selective, covalent TEAD autopalmitoylation inhibitor with the IC50 value of 197 ± 19 nM while it showed minimal effect on TEAD-YAP interaction. Further biochemical counter-screens demonstrate the specific thiol reactivity and selectivity of DC-TEADin02 over the kinase family, lipid-binding proteins and epigenetic targets. Notably, DC-TEADin02 inhibited TEADs transcription activity leading to downregulation of YAP-related downstream gene expression. Taken together, our findings proved the validity of modulating transcriptional output in the Hippo signaling pathway through irreversible chemical interventions of TEADs autopalmitoylation activity, which may serve as a qualified chemical tool for TEADs palmitoylation-related studies in the future.
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