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
  • 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: [email protected].
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.
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-125269
    TED-347
    99.13%, YAP-TEAD Inhibitor
    target: YAP
    Research Areas: Cancer