Molecular Glue Degraders in Early Development for Cancer Therapy.

Abstract

Molecular glue degraders are an emerging class of small molecule allosteric modulators that induce or stabilize protein-protein interactions, enabling targeted degradation of previously intractable proteins. By redirecting E3 ligases to recognize neosubstrates, proteins that are not typically recognized by a specific E3 ubiquitin ligase, they expand the scope of drug discovery beyond traditional paradigms. We review mechanistic principles underlying molecular glue activity, including cooperativity, weak affinity interactions, structural degrons, and higher-order complex formation. We discuss discovery strategies, from serendipitous identification to emerging rational and chemoproteomic approaches, and key E3 ligase systems with relevance to oncology. We highlight clinical and preclinical applications, alongside challenges such as resistance mechanisms, context-dependent activity, and limitations in predicting neosubstrates. Molecular glues are transitioning from serendipitous discoveries to a mechanism-driven therapeutic platform. Progress depends on integrating structural biology, proteomics, and computational modeling to enable rational design and improve predictability. Expanding the repertoire of E3 ligases and understanding context-specific degradation will be critical to fully realize their potential in oncology and beyond.