Finding a needle in the haystack: ADME and pharmacokinetics/pharmacodynamics characterization and optimization towards orally available bifunctional protein degraders

IntroductionDegraders are an increasingly important sub-modality of small molecules as illustrated by an ever-expanding number of publications and clinical candidate molecules in human trials. Nevertheless, their preclinical optimization of ADME and PK/PD properties has remained challenging. Significant research efforts are being directed to elucidate the underlying principles and to derive rational optimization strategies.Areas coveredIn this review, the authors summarize currently best practices in terms of in vitro assays and in vivo experiments. Furthermore, the authors collate and comment on the current understanding of optimal physicochemical characteristics and their impact on absorption, distribution, metabolism, and excretion properties, including the current knowledge of drug-rug interactions. Finally, the authors describe the pharmacokinetic prediction and Pharmacokinetic/Pharmacodynamic -concepts unique to degraders and how to best implement these in research projects.Expert opinionDespite many recent advances in the field, continued research will further our understanding of rational design regarding degrader optimization. Machine-learning and computational approaches will become increasingly important once larger, more robust datasets become available. Furthermore, tissue-targeting approaches (particularly regarding the central nervous system will be increasingly studied to elucidate efficacious drug regimens that capitalize on the catalytic mode of action. Finally, additional specialized approaches (e.g. covalent degraders, LOVdegs) can further enrich the field and offer interesting alternative approaches.