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 Corson, Karen Pollok, Clark Wells, Samy Meroueh

Research output: Contribution to journalArticle

6 Citations (Scopus)

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

Fingerprint

Palmitates
Glioblastoma
Cysteine
Cell Survival
Cells
Connective Tissue Growth Factor
Molecules
Covalent bonds
Organ Size
Tissue homeostasis
Proteins
Homeostasis
Transcription Factors
Neoplasms

Keywords

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

ASJC Scopus subject areas

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

Cite this

Small-Molecule Covalent Modification of Conserved Cysteine Leads to Allosteric Inhibition of the TEAD⋅Yap Protein-Protein Interaction. / Bum-Erdene, Khuchtumur; Zhou, Donghui; Gonzalez-Gutierrez, Giovanni; Ghozayel, Mona K.; Si, Yubing; Xu, David; Shannon, Harlan E.; Bailey, Barbara J.; Corson, Timothy; Pollok, Karen; Wells, Clark; Meroueh, Samy.

In: Cell Chemical Biology, Vol. 26, No. 3, 21.03.2019, p. 378-389.e13.

Research output: Contribution to journalArticle

Bum-Erdene, Khuchtumur ; Zhou, Donghui ; Gonzalez-Gutierrez, Giovanni ; Ghozayel, Mona K. ; Si, Yubing ; Xu, David ; Shannon, Harlan E. ; Bailey, Barbara J. ; Corson, Timothy ; Pollok, Karen ; Wells, Clark ; Meroueh, Samy. / Small-Molecule Covalent Modification of Conserved Cysteine Leads to Allosteric Inhibition of the TEAD⋅Yap Protein-Protein Interaction. In: Cell Chemical Biology. 2019 ; Vol. 26, No. 3. pp. 378-389.e13.
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