Abstract
Many essential biological processes are regulated through proximity, from membrane receptor signaling to transcriptional activity. The ubiquitin-proteasome system controls protein degradation, with ubiquitin ligases as the rate-limiting step. Ubiquitin ligases are commonly controlled at the level of substrate recruitment and, therefore, by proximity. There are natural and synthetic small molecules that also operate through induced proximity. For example, thalidomide is effective in treating multiple myeloma and functions as a molecular glue that stabilizes novel protein-protein interactions between a ubiquitin ligase and proteins not otherwise targeted by the ligase, leading to neo-substrate degradation. Emerging data on new degrader molecules have uncovered diverse mechanisms distinct from molecular glues, which often mirror the regulatory mechanisms that control substrate-ligase proximity in nature. In this review, we summarize our current understanding of biological and synthetic regulation of protein degradation and share our view on how these diverse mechanisms have inspired novel therapeutic directions.
Highlights
Targeted protein degradation (TPD) is a rapidly evolving concept in drug discovery
The ability to alter the specificity of E3 ubiquitin ligases with small molecules and redirect them to proteins linked to disease is an exciting area for therapeutic expansion
A GSPT1 degrader, CC-90009, has been reported to be in phase I clinical trials in acute myeloid leukemia (AML) (Surka et al 2020). All of these examples clearly demonstrate that alterations to the surface-exposed features of the small molecule (Figure 3b) can dramatically impact the neo-substrate profile of CRBN, both for the C2H2 transcription factors and for other targets, and they indicate that the rational design of molecular glues targeting selected proteins of interest is within reach
Summary
By using small molecules (commonly referred to as degraders) to redirect the cellular machinery to destroy specific proteins, researchers have the opportunity to discover powerful new therapeutics in multiple disease areas. Given the energetically expensive nature of ubiquitin-dependent degradation and protein resynthesis, many regulatory mechanisms have evolved to precisely control access of a substrate to its cognate ligase (Figure 1). These mechanisms include PTM, protein quality control, substrate oligomerization, and ligand binding. The ability to alter the specificity of E3 ubiquitin ligases with small molecules and redirect them to proteins linked to disease is an exciting area for therapeutic expansion. We contrast new synthetic modalities of TPD with biological UPS regulatory mechanisms in health and disease, and we consider their future therapeutic potential in the context of past and current clinical development
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