Enabling cancer target validation with genetically encoded systems for ligand-induced protein degradation

Abstract

Recent technological advances have improved the ability of functional genetic approaches to discover new targets for anti-cancer therapeutics. At the same time, advances in discovery chemistry promise to deliver on an ever-larger fraction of these new targets. However, the fundamental difference in the kinetics of genetic and chemical perturbations can make it difficult to judge the performance of new chemical tools when only genetic information is available. Here, we review a series of genetically encoded, ligand-inducible protein degradation systems that can bridge the gap between genetics and pharmacology. These approaches rely on tagging a protein of interest with a small-molecule-responsive degron that enables conditional protein degradation. Given their rapid effects, these systems can facilitate mechanistic interpretations that are not typically possible using traditional genetic approaches. Therefore, inducible degradation systems can be employed at the earliest stages of target validation to provide mechanistic insights that will better guide future drug discovery efforts.