Browsing by Subject "Hippo signaling"

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    Small-Molecule Covalent Modification of Conserved Cysteine Leads to Allosteric Inhibition of the TEAD⋅Yap Protein-Protein Interaction
    (Elsevier, 2019) Bum-Erdene, Khuchtumur; Zhou, Donghui; Gonzalez-Gutierrez, Giovanni; Ghozayel, Mona K.; Si, Yubing; Xu, David; Shannon, Harlan E.; Bailey, Barbara J.; Corson, Timothy W.; Pollok, Karen E.; Wells, Clark D.; Meroueh, Samy O.; Biochemistry and Molecular Biology, School of Medicine
    The 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.