Rai Lecture Award: Engineering Protein Destruction: The Biology and Therapeutic Promise of BTK Degraders/ PROTACs

The emergence of BTK degraders and proteolysis-targeting chimeras (PROTACs) represents a novel therapeutic strategy designed to overcome limitations of conventional BTK inhibition. Rather than inhibiting kinase activity alone, these agents harness the cell’s protein degradation machinery to selectively eliminate BTK, including mutant forms associated with resistance to both covalent and noncovalent BTK inhibitors. This session will review the biologic rationale underlying targeted protein degradation, the evolving clinical data for BTK degraders in relapsed and refractory B-cell malignancies, and the potential impact of this approach on treatment sequencing. Faculty will discuss emerging efficacy and safety data, resistance mechanisms, combination strategies, and future opportunities to integrate BTK degraders into precision treatment paradigms. Attendees will gain practical insights into the therapeutic promise of protein destruction as the next frontier in BTK-directed therapy.