PROTAC-Mediated Targeting of PARP via CRBN: Mechanistic Insights, Resistance Challenges, and Therapeutic Advancements

Abstract: Proteolysis-targeting chimeras (PROTACs) have become a game-changing mode of therapeutic intervention capable of turning off disease-driving proteins by using the ubiquitinproteasome system. In contrast to conventional inhibitors, PROTACs act through event-driven pharmacology and, by providing comprehensive clearance of targeted proteins, they promise to address resistance mechanisms that plague conventional therapies. This review discusses the paradigm- shifting potential of PROTACs to degrade poly (ADP-ribose) polymerases (PARPs), key regulatory enzymes in the DNA damage response whose inhibition has been clinically validated in BRCA-mutant cancers. Nevertheless, resistance to PARP inhibitors has led to the need for alternative approaches, and PROTACs have become a potent strategy to degrade PARP via the proteasome. A key component of this strategy is Cereblon (CRBN), which is a commonly utilized E3 ligase in the design of PROTACs and is considered highly druggable and expressed. We unravel the molecular actions that are the basis of CRBN-directed protein degradation and address the existing issues, such as ligase saturation, resistance through mutations, and off-target signatures, as well as translational challenges of PROTAC technology, such as pharmacokinetics, cell permeability, and potential toxicity. Moreover, we demonstrate emerging technologies such as dual-ligase PROTACs, AI-based ligand optimization, and deep mutational scanning as methods to enhance degrader space and target efficacy. This review combines insights on the mechanisms with upcoming technologies to propose important prospects and future research gaps in E3 ligase selection, degrader specificity, and resistance management. Together, we introduce PARP-targeting PROTACs, in collaboration with CRBN, as a promising area of precision drug development and oncology.