Targeted Protein Stabilization Platforms

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A major challenge in developing new cancer therapies is that most, >90 %, of the proteome is considered “undruggable.” This implies that most proteins are devoid of characterized, functional binding pockets, or “druggable hotspots,” that small molecules can bind to modulate a protein’s function for therapeutic benefit. Developing new disease therapies therefore requires novel therapeutic modalities and drug discovery paradigms for uncovering new, unique ways to alter protein function of traditionally “undruggable” proteins. Targeted protein degradation (TPD) using proteolysis-targeting chimeras (PROTACs) has arisen as a powerful modality for tackling the undruggable proteome by targeting specific proteins for ubiquitination and proteasomal degradation. PROTACs, heterobifunctional small molecules consisting of a protein-targeting ligand linked to an E3 ligase recruiter, act through inducing formation of ternary complexes that bring together an E3 ubiquitin ligase with a neo-substrate protein target to polyubiquitinate and degrade specific targets of interest. While TPD is an incredibly powerful platform for degrading potentially any disease-causing protein in cells, there are many proteins that are actively ubiquitinated and degraded to cause disease. In these cases, targeted protein deubiquitination and stabilization, instead of degradation, could represent a viable therapeutic strategy. Proteins that are actively ubiquitinated and degraded to cause disease pathogenesis include tumor suppressors TP53, CDKN1A (p21), CDKN1C (p57), BAX, and axin in cancer, or mutant CFTR in cystic fibrosis, and stabilization of these proteins through deubiquitination could be beneficial. Developing a Deubiquitinase Targeting Chimera (DubTAC) platform for targeted protein stabilization (TPS) that utilizes heterobifunctional small molecules linking deubiquitinase (DUB) recruiters to protein-targeting ligands would enable a new therapeutic modality for stabilizing and increasing expression of proteasomally-degraded proteins. In this proposal I will utilize chemoproteomics-enabled covalent ligand discovery platforms to develop a DubTAC platform for TPS, through recruiting DUBs to specific neo-substrates for targeted deubiquitination and stabilization of protein targets for therapeutic benefit.