2. Academic Validation
  3. Small-Molecule Covalent Modification of Conserved Cysteine Leads to Allosteric Inhibition of the TEAD⋅Yap Protein-Protein Interaction

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

  • Cell Chem Biol. 2019 Mar 21;26(3):378-389.e13. doi: 10.1016/j.chembiol.2018.11.010.
Khuchtumur Bum-Erdene 1,  Donghui Zhou 1,  Giovanni Gonzalez-Gutierrez 2,  Mona K Ghozayel 1,  Yubing Si 1,  David Xu 3,  Harlan E Shannon 4,  Barbara J Bailey 4,  Timothy W Corson 5,  Karen E Pollok 4,  Clark D Wells 1,  Samy O Meroueh 6
Affiliations

Affiliations

  • 1 Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
  • 2 Department of Molecular and Cellular Biochemistry, Indiana University, Bloomington, IN 47405, USA.
  • 3 Department of BioHealth Informatics, Indiana University School of Informatics and Computing, Indianapolis, IN 46202, USA.
  • 4 Department of Pediatrics, Herman B. Wells Center for Pediatric Research, Indiana University Simon Cancer Center, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
  • 5 Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN 46202, USA; Eugene and Marilyn Glick Eye Institute, Department of Ophthalmology, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
  • 6 Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN 46202, USA. Electronic address: smeroueh@iu.edu.
PMID: 30581134 DOI: 10.1016/j.chembiol.2018.11.010
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.

Keywords

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

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-125269
    98.97%, YAP-TEAD 抑制剂
    YAP
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