2. Academic Validation
  3. Exploring Degradation of Intrinsically Disordered Protein Yes-Associated Protein Induced by Proteolysis TArgeting Chimeras

Exploring Degradation of Intrinsically Disordered Protein Yes-Associated Protein Induced by Proteolysis TArgeting Chimeras

  • J Med Chem. 2024 Sep 12;67(17):15168-15198. doi: 10.1021/acs.jmedchem.4c00815.
Chen Zhou 1,  Chunbao Sun 2,  Miao Huang 3 4,  Xin Tang 3 4 5,  Liya Pi 2,  Chenglong Li 1
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 Mechanical and Aerospace Engineering, Herbert Wertheim College of Engineering, University of Florida, Gainesville, Florida 32610, United States.
  • 4 UF Health Cancer Center, University of Florida, Gainesville, Florida 32610, United States.
  • 5 J. Crayton Pruitt Family Department of Biomedical Engineering, University of Florida, Gainesville, Florida 32610, United States.
PMID: 39189384 DOI: 10.1021/acs.jmedchem.4c00815
Abstract

Yes-associated protein (YAP) is a key oncogene in the Hippo tumor suppression pathway, historically challenging to target due to its intrinsically disordered nature. Leveraging recent advances in high-throughput screening that identified several YAP binders, we employed proteolysis-targeting chimera technology to develop a series of YAP degraders. Utilizing NSC682769, a known YAP binder, linked with VHL ligand 2 or pomalidomide via diverse linkers, we synthesized degraders including YZ-6. This degrader not only recruits the E3 Ligase VHL for the rapid and sustained degradation of YAP but also effectively inhibits its nuclear localization, curtailing YAP/TEAD-mediated transcription in Cancer cell lines such as NCI-H226 and Huh7. This dual action significantly diminishes YAP's oncogenic activity, contributing to the potent antiproliferative effects observed both in vitro and in a Huh7 xenograft mouse model. These results underscore the potential of PROTAC-mediated YAP degradation as a strategy for treating YAP-driven cancers.

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