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Updated: Jun 15, 2025

Author Spotlight: Evaluating Biophysical Assays for Characterizing PROTACS Ternary Complexes
Published on: January 12, 2024
Exploring Degradation of Intrinsically Disordered Protein Yes-Associated Protein Induced by Proteolysis TArgeting
Chen Zhou1, Chunbao Sun2, Miao Huang3,4
1Department of Medicinal Chemistry, College of Pharmacy, University of Florida, Gainesville, Florida 32610, United States.
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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