Chapter 12: Small-molecule-mediated Targeted Protein Degradation for Drug Discovery

Recent advances in small-molecule mediated protein degradation have fueled interest in applying such technology to drug development. Whereas conventional therapeutics require sustained target occupancy to ensure maximal clinical effect, induced protein degradation operates via an event driven model in which the drug, through a catalytic mechanism, mediates recruitment of the target protein to the cellular quality control machinery. Targeted protein degradation offers the potential of a new class of drug molecules, advantageous in terms of potency, efficacy, duration of action and target selection in comparison to traditional occupancy based therapeutics. Recent findings in the development of small molecule heterobifunctional degraders (which recruit target proteins to an E3 ubiquitin ligase) have positioned this technology front and center for taking on this therapeutic challenge. Such bifunctional degraders have demonstrated potent, selective and reversible protein depletion of a number of cellular protein targets. There are however a number of factors that play a role in what makes an optimal degrader and what defines an ideal target for this technology. This chapter discusses recent progress in the development of heterobifunctional degraders, assesses the scope and limitations of the technology, and touches on other emerging concepts in the area of small-molecule mediated targeted protein degradation.