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.
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