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Author Spotlight: Evaluating Biophysical Assays for Characterizing PROTACS Ternary Complexes
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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.
Journal of Medicinal Chemistry
|August 27, 2024
Summary
Scientists developed novel degraders targeting Yes-associated protein (YAP) using proteolysis-targeting chimera technology. These degraders effectively reduce YAP oncogenic activity, showing promise for treating YAP-driven cancers.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Yes-associated protein (YAP) is a key oncogene in the Hippo pathway.
- YAP's intrinsically disordered nature presents challenges for traditional drug targeting.
- Recent advances identified YAP binders, enabling new therapeutic strategies.
Purpose of the Study:
- To develop proteolysis-targeting chimera (PROTAC) degraders for YAP.
- To assess the efficacy of these degraders in inhibiting YAP activity and proliferation.
Main Methods:
- Utilized proteolysis-targeting chimera (PROTAC) technology.
- Synthesized YAP degraders by linking YAP binders (e.g., NSC682769) with E3 ligase ligands (VHL ligand 2, pomalidomide).
- Evaluated degrader efficacy in cancer cell lines (NCI-H226, Huh7) and a xenograft mouse model.
Main Results:
- Developed novel YAP degraders, including YZ-6, that induce rapid and sustained YAP degradation.
- Degraders inhibited YAP nuclear localization and YAP/TEAD-mediated transcription.
- Demonstrated potent antiproliferative effects in vitro and in vivo, reducing tumor growth in a Huh7 xenograft model.
Conclusions:
- PROTAC-mediated YAP degradation is a viable strategy for targeting YAP-driven cancers.
- The developed degraders show significant potential for cancer therapy.
- This approach overcomes challenges associated with targeting intrinsically disordered proteins like YAP.
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