Discovery and biological evaluation of vinylsulfonamide derivatives as highly potent, covalent TEAD autopalmitoylation inhibitors.

Discovery and biological evaluation of vinylsulfonamide derivatives as highly potent, covalent TEAD autopalmitoylation inhibitors.
Eur J Med Chem. 2019 Oct 09;184:111767
Authors: Lu W, Wang J, Li Y, Tao H, Xiong H, Lian F, Gao J, Ma H, Lu T, Zhang D, Ye X, Ding H, Yue L, Zhang Y, Tang H, Zhang N, Yang Y, Jiang H, Chen K, Zhou B, Luo C
Abstract
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...

Source: European Journal of Medicinal Chemistry - October 8, 2019 Category: Chemistry Authors: Lu W, Wang J, Li Y, Tao H, Xiong H, Lian F, Gao J, Ma H, Lu T, Zhang D, Ye X, Ding H, Yue L, Zhang Y, Tang H, Zhang N, Yang Y, Jiang H, Chen K, Zhou B, Luo C Tags: Eur J Med Chem Source Type: research