Stapled Peptide Degraders for Pediatric Cancer Therapy
Mentor: Dr. Loren Walensky
Proteolysis targeting chimeras (PROTACs) have emerged as promising candidate therapeutics based on their capacity to bind and degrade oncogenic proteins, harnessing the ubiquitin proteosomal pathway. Despite the tremendous excitement about the translational potential of PROTACs, considerable limitations remain, including (1) the complexity and unpredictability of factors required to ensure dual and effective engagement of oncogenic target and E3 ligase (e.g. orientation of the two ligands, size and character of linker, etc.); (2) the cellular uptake of the relatively large PROTAC molecules; and (3) the limited number of E3 ligases currently engaged by PROTACs. As a POST student, I would contribute this summer to a project designed to harness the unique attributes of stapled peptides to generate stapled peptide degraders for pediatric cancer therapy. The unique aspects of our approach include the capacity of stapled peptides to (1) engage protein interaction surfaces that are large, flat and complex and otherwise poor substrates for small molecule development; (2) serve an additional role as a cell import modality; and (3) recruit underexplored E3 ligases for targeted protein degradation. We believe that the union of stapled peptides and small molecules in this fashion will open an entirely new opportunity to generate alternative PROTACs for treating chemoresistant pediatric cancers.
