Bum-Erdene, KhuchtumurZhou, DonghuiGonzalez-Gutierrez, GiovanniGhozayel, Mona K.Si, YubingXu, DavidShannon, Harlan E.Bailey, Barbara J.Corson, Timothy W.Pollok, Karen E.Wells, Clark D.Meroueh, Samy O.2019-12-312019-12-312019Bum-Erdene, K., Zhou, D., Gonzalez-Gutierrez, G., Ghozayel, M. K., Si, Y., Xu, D., … Meroueh, S. O. (2019). Small-Molecule Covalent Modification of Conserved Cysteine Leads to Allosteric Inhibition of the TEAD⋅Yap Protein-Protein Interaction. Cell Chemical Biology, 26(3), 378-389.e13. https://doi.org/10.1016/j.chembiol.2018.11.010https://hdl.handle.net/1805/21639The Hippo pathway coordinates extracellular signals onto the control of tissue homeostasis and organ size. Hippo signaling primarily regulates the ability of Yap1 to bind and co-activate TEA domain (TEAD) transcription factors. Yap1 tightly binds to TEAD4 via a large flat interface, making the development of small-molecule orthosteric inhibitors highly challenging. Here, we report small-molecule TEAD⋅Yap inhibitors that rapidly and selectively form a covalent bond with a conserved cysteine located within the unique deep hydrophobic palmitate-binding pocket of TEADs. Inhibition of TEAD4 binding to Yap1 by these compounds was irreversible and occurred on a longer time scale. In mammalian cells, the compounds formed a covalent complex with TEAD4, inhibited its binding to Yap1, blocked its transcriptional activity, and suppressed expression of connective tissue growth factor. The compounds inhibited cell viability of patient-derived glioblastoma spheroids, making them suitable as chemical probes to explore Hippo signaling in cancer.enPublisher Policycovalent bondHippo signalingcancerArticle