Chemical Degradation of Disease-related Proteins: Discovery and Challenge for Drug Discovery

Abstract

New therapeutic modalities are needed to address the problem of pathological but undruggable proteins. One emerging technology is small molecules that shorten lifespan of disease-related proteins. This article reviews induction of proteasomal degradation of the target proteins by hybrid small molecules composed of a ubiquitin ligase ligand coupled to a ligand for the target protein. This article also describes recent efforts towards undruggable proteins such as substrate binding proteins and aggregation-prone proteins, and the challenges for drug discovery.