2. Academic Validation
  3. Structure-Based Design of Y-Shaped Covalent TEAD Inhibitors

Structure-Based Design of Y-Shaped Covalent TEAD Inhibitors

  • J Med Chem. 2023 Apr 13;66(7):4617-4632. doi: 10.1021/acs.jmedchem.2c01548.
Wenchao Lu 1,  Mengyang Fan 2,  Wenzhi Ji 1,  Jason Tse 1,  Inchul You 1,  Scott B Ficarro 3,  Isidoro Tavares 3,  Jianwei Che 4,  Audrey Y Kim 1,  Xijun Zhu 5,  Andrew Boghossian 6,  Matthew G Rees 6,  Melissa M Ronan 6,  Jennifer A Roth 6,  Stephen M Hinshaw 1,  Behnam Nabet 7,  Steven M Corsello 8,  Nicholas Kwiatkowski 4,  Jarrod A Marto 3 9,  Tinghu Zhang 1,  Nathanael S Gray 1
Affiliations

Affiliations

  • 1 Department of Chemical and Systems Biology, Chem-H and Stanford Cancer Institute, Stanford School of Medicine, Stanford University, Stanford, California 94305, United States.
  • 2 Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, Zhejiang 310022, China.
  • 3 Department of Cancer Biology, Blais Proteomics Center, Center for Emergent Drug Targets, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, United States.
  • 4 Center for Protein Degradation, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, United States.
  • 5 Department of Chemistry, Stanford University, Stanford, California 94305, United States.
  • 6 Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, United States.
  • 7 Human Biology Division, Fred Hutchinson Cancer Center, Seattle, Washington 98109, United States.
  • 8 Department of Medicine and Stanford Cancer Institute, Stanford School of Medicine, Stanford University, Stanford, California 94305, United States.
  • 9 Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02215, United States.
PMID: 36946421 DOI: 10.1021/acs.jmedchem.2c01548
Abstract

Transcriptional enhanced associate domain (TEAD) proteins together with their transcriptional coactivator yes-associated protein (YAP) and transcriptional coactivator with the PDZ-binding motif (TAZ) are important transcription factors and cofactors that regulate gene expression in the Hippo pathway. In mammals, the TEAD families have four homologues: TEAD1 (TEF-1), TEAD2 (TEF-4), TEAD3 (TEF-5), and TEAD4 (TEF-3). Aberrant expression and hyperactivation of TEAD/YAP signaling have been implicated in a variety of malignancies. Recently, TEADs were recognized as being palmitoylated in cells, and the lipophilic palmitate pocket has been successfully targeted by both covalent and noncovalent ligands. In this report, we present the medicinal chemistry effort to develop MYF-03-176 (compound 22) as a selective, cysteine-covalent TEAD inhibitor. MYF-03-176 (compound 22) significantly inhibits TEAD-regulated gene expression and proliferation of the cell lines with TEAD dependence including those derived from mesothelioma and liposarcoma.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-147136
    99.52%, TEAD Inhibitor
    YAP