Emerging mechanisms of targeted protein degradation by molecular glues

Abstract

Targeted protein degradation has emerged as a transformative therapeutic modality for the treatment of human diseases. The clinical successes of approved protein degraders like lenalidomide and thalidomide in cancers and immune disorders, combined with the recent clinical debut of investigational heterobifunctional degraders, have demonstrated the potential of this pharmacological approach to expand the druggable proteome and improve patient outcomes. Molecular glue degraders are a class of protein degraders that operate by recruiting target proteins to cellular degradation machinery via noncanonical protein-protein interactions, inducing the destruction of the target protein. While heterobifunctional degraders consist of two distinct protein-binding moieties connected by a linker, molecular glue degraders contain a single pharmacophore and are thus more synthetically accessible, ligand-efficient, and often possess more drug-like physicochemical properties. In this chapter, we will explore the history of the field-from its conception to the recently accelerating discovery of novel glue degrader mechanisms-and contemplate its trajectory towards rational design with the emergence of new methods for protein quantification and high-throughput assays to screen for novel degraders.

Keywords: Chemically induced proximity; E3 ligase; Molecular glues; Monovalent; Protein degraders; Targeted protein degradation; Ubiquitin.