Harnessing E3 Ligases for Cancer Therapy

Targeted protein degradation (TPD) has arisen as a powerful therapeutic modality for degrading and eliminating cancer-causing proteins and has enabled potential access into classically undruggable protein targets. Two main TPD approaches currently employed include heterobifunctional Proteolysis Targeting Chimeras (PROTACs) and monovalent molecular glue degraders that both use small-molecules to induce the proximity of E3 ubiquitin ligases with target proteins to ubiquitinate and degrade specific disease targets of interest. However, there are still major bottlenecks in realizing the full potential of TPD platforms. In this proposal, we will overcome bottlenecks in cancer drug discovery by developing innovative next-generation approaches for TPD using covalent chemoproteomic strategies, including expanding upon rational chemical design strategies to discover molecular glue degraders and uncover permissive E3 ligases for TPD applications and covalently targeting and destabilizing undruggable oncogenic transcription factors.