Translational PK-PD for targeted protein degradation.

Abstract

Targeted protein degradation has emerged from the chemical biology toolbox as one of the most exciting areas for novel therapeutic development across the pharmaceutical industry. The ability to induce the degradation, and not just inhibition, of target proteins of interest (POIs) with high potency and selectivity is a particularly attractive property for a protein degrader therapeutic. However, the physicochemical properties and mechanism of action for protein degraders can lead to unique pharmacokinetic (PK) and pharmacodynamic (PD) properties relative to traditional small molecule drugs, requiring a shift in perspective for translational pharmacology. In this review, we provide practical insights for building the PK-PD understanding of protein degraders in the context of translational drug development through the use of quantitative mathematical frameworks and standard experimental assays. Published datasets describing protein degrader pharmacology are used to illustrate the applicability of these insights. The learnings are consolidated into a translational PK-PD roadmap for targeted protein degradation that can enable a systematic, rational design workflow for protein degrader therapeutics.