Abstract A054: Molecular glue discovery enabled by targeted degron display

Abstract

Small molecules that induce protein interactions hold tremendous potential as new medicines, as probes for molecular pathways, and as tools for agriculture. Explosive growth of targeted protein degradation drug development has spurred renewed interest in proximity inducing molecules and especially molecular glue degraders. These compounds catalyze destruction of disease-causing proteins by reshaping protein surfaces and promoting cooperative binding between ubiquitylating enzymes and target proteins. Molecular glue discovery for pre-defined targets is a major challenge in contemporary drug discovery. Here I will discuss how we address these important chemical challenges through molecular glue discovery enabled by targeted degron display. By leveraging mechanisms such as electrophilic covalent bonding, electrostatic interactions, or cation-pi interactions, I have identified a range of potent molecular glue degraders that recruit previously unligandable ubiquitylating factors for multiple therapeutically relevant epigenetic regulators and kinases. This "chemocentric" approach provides a powerful strategy to discover molecular glues that induce proximity to ubiquitin ligases with similarly desirable properties. Zhe Zhuang. Molecular glue discovery enabled by targeted degron display [abstract]. In: Proceedings of AACR Drug Discovery and Development (AACR D3) Conference; 2026 Jul 21-24; Boston, MA. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(14_Suppl):Abstract nr A054.