Emerging pharmacology of targeted protein degraders

Targeted protein degradation is an emerging strategy for experimental and therapeutic ablation of biologically important proteins. To elicit the degradation of their cellular targets, targeted protein degraders act by co-opting the endogenous cellular degradation machineries through chemically-induced proximity. While targeted protein degradation was serendipitously discovered as the mode of action of approved anticancer drugs including fulvestrant and thalidomide, recent years have witnessed systematic endeavors for the rational design of targeted protein degraders for diverse biological targets. Such endeavors have led to 3 major classes of targeted protein degraders including molecular glue degraders, proteolysis targeting chimeras, and hydrophobic tag-based degraders. Of these, several agents are clinically approved or currently evaluated in clinical trials for use in diseases such as cancer, neurodegenerative disorders, autoimmune and dermatologic conditions. The novel chemical and pharmacologic nature of targeted protein degraders heralds an emerging paradigm of pharmacology, known as event-driven pharmacology, which is different in many aspects from the occupancy-based pharmacology of conventional small-molecule inhibitors. In this review, we discuss the emerging pharmacology of different classes of targeted protein degraders including the molecular basis of their drug action and key pharmacologic properties pertinent to efficacy, selectivity, safety, and dosing considerations. SIGNIFICANCE STATEMENT: Targeted protein degradation is a novel strategy that establishes induced-proximity pharmacology as a promising next-generation therapeutic modality. This review provides insights into the common organizing principles of this emerging approach and the prospects for this rapidly evolving field.