2. Academic Validation
  3. Development of Novel Indole-Based Covalent Inhibitors of TEAD as Potential Antiliver Cancer Agents

Development of Novel Indole-Based Covalent Inhibitors of TEAD as Potential Antiliver Cancer Agents

  • J Med Chem. 2024 Sep 26;67(18):16270-16295. doi: 10.1021/acs.jmedchem.4c00925.
Chen Zhou 1,  Chunbao Sun 2,  Wei Zhou 3,  Tian Tian 2,  Daniel C Schultz 1,  Tong Wu 2,  Mu Yu 4 5,  Lizi Wu 4 5 6,  Liya Pi 2,  Chenglong Li 1 3 7
Affiliations

Affiliations

  • 1 Department of Medicinal Chemistry, College of Pharmacy, University of Florida, Gainesville, Florida 32610, United States.
  • 2 Department of Pathology and Laboratory Medicine, School of Medicine, Tulane University, New Orleans, Louisiana 70112, United States.
  • 3 Department of Biochemistry and Molecular Biology, College of Medicine, University of Florida, Gainesville, Florida 32610, United States.
  • 4 Department of Molecular Genetics and Microbiology, University of Florida, Gainesville, Florida 32610, United States.
  • 5 UF Health Cancer Center, University of Florida, Gainesville, Florida 32610, United States.
  • 6 UF Institute of Genetics, University of Florida, Gainesville, Florida 32610, United States.
  • 7 Center for Natural Products, Drug Discovery and Development (CNPD3), College of Pharmacy, University of Florida, Gainesville, Florida 32610, United States.
PMID: 39270302 DOI: 10.1021/acs.jmedchem.4c00925
Abstract

Abnormal activation of the YAP transcriptional signaling pathway drives proliferation in many hepatocellular carcinoma (HCC) and hepatoblastoma (HB) cases. Current treatment options often face resistance and toxicity, highlighting the need for alternative therapies. This article reports the discovery of a hit compound C-3 from docking-based virtual screening targeting TEAD lipid binding pocket, which inhibited TEAD-mediated transcription. Optimization led to the identification of a potent and covalent inhibitor CV-4-26 that exhibited great antitumor activity in HCC and HB cell lines in vitro, xenografted human HCC, and murine HB in vivo. These outcomes signify the potential of a highly promising therapeutic candidate for addressing a subset of HCC and HB cancers. In the cases of current treatment challenges due to high upregulation of YAP-TEAD activity, these findings offer a targeted alternative for more effective interventions against liver Cancer.

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