From serendipity to strategy: molecular glue degraders in cancer therapeutics.

Abstract

Targeted protein degradation is an elegant therapeutic strategy that harnesses the cell's own degradation machinery to selectively eliminate target proteins. This approach marks a paradigm shift in drug discovery, moving beyond traditional occupancy-based inhibition toward target degradation, thereby silencing proteins that have historically resisted pharmacological intervention. Degrader molecules function by inducing proximity between target proteins and effectors, most commonly E3 ubiquitin ligases, triggering their ubiquitylation and proteasomal degradation. Molecular glue degraders - monovalent small molecules that promote these neo-interactions - have emerged as powerful tools in this space. Serendipity was once synonymous with molecular glue discovery, but increasing mechanistic understanding is now guiding their rational design. In this review, we trace their evolution from chance discovery, explore the biological mechanisms that underpin molecular glue activity, examine key examples that have advanced into the clinic, and discuss the challenges that remain in harnessing these compounds for broader therapeutic impact.