Small-Molecule Covalent Modification of Conserved Cysteine Leads to Allosteric Inhibition of the TEAD⋅Yap Protein-Protein Interaction

Khuchtumur Bum-Erdene, Donghui Zhou, Giovanni Gonzalez-Gutierrez, Mona K. Ghozayel, Yubing Si, David Xu, Harlan E. Shannon, Barbara J. Bailey, Timothy W. Corson, Karen E. Pollok, Clark D. Wells, Samy O. Meroueh

Research output: Contribution to journalArticle

13 Scopus citations

Abstract

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. A small molecule that forms a covalent bond with a conserved cysteine within the palmitate binding pocket of TEADs was found to inhibit the TEAD⋅Yap protein-protein interaction through allostery. The compound inhibited TEAD transcriptional activity in mammalian cells and blocked patient-derived glioblastoma cell viability.

Original languageEnglish (US)
Pages (from-to)378-389.e13
JournalCell Chemical Biology
Volume26
Issue number3
DOIs
StatePublished - Mar 21 2019

Keywords

  • Hippo signaling
  • TEAD transcription factor
  • Yap co-activator
  • allosteric inhibitors
  • covalent inhibitors
  • protein-protein interaction inhibitors
  • small-molecule inhibitors

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmacology
  • Drug Discovery
  • Clinical Biochemistry

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