Targeted Protein Degradation by Small Molecules

Abstract

Protein homeostasis networks are highly regulated systems responsible for maintaining the health and productivity of cells. Whereas therapeutics have been developed to disrupt protein homeostasis, more recently identified techniques have been used to repurpose homeostatic networks to effect degradation of disease-relevant proteins. Here, we review recent advances in the use of small molecules to degrade proteins in a selective manner. First, we highlight all-small-molecule techniques with direct clinical application. Second, we describe techniques that may find broader acceptance in the biomedical research community that require little or no synthetic chemistry. In addition to serving as innovative research tools, these new approaches to control intracellular protein levels offer the potential to develop novel therapeutics targeting proteins that are not currently pharmaceutically vulnerable.

Keywords: IMiDs; PROTACs; chemical knockdown; protein degradation; ubiquitin proteasome system.

Figure 1

Compounds that degrade their respective targets without requiring any genetic manipulation. The substrate binding portion is highlighted in yellow, whereas purple dictates parts of the compound that induce target protein degradation. (a) ARN-810, a bioavailable SERD that causes degradation upon rearrangement of hydrophobic portions of ERα by the vinyl carboxylic acid. Minor changes at the carboxylic acid position can create ERα agonists. (b) Lenalidomide, an immunomodulatory compound that causes degradation of Ikaros and CK1α by binding to the E3 ligase cereblon and creating a novel surface for their interaction. Minor structural changes in the compound abrogate CK1α binding but maintain Ikaros binding. (c) A PROTAC induces degradation of RIPK2 by recruiting it to the E3 ligase VHL. The two binding motifs are separated by the linker, allowing enhanced modularity. Abbreviations: CK1α, casein kinase 1α; ERα, estrogen receptor α; PROTAC, proteolysis targeting chimera; RIPK2, receptor interacting serine/threonine kinase 2; SERD, selective estrogen receptor downregulator; SERM, selective estrogen receptor modulator; VHL, von Hippel–Lindau.