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 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. 

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 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. 

Compared to ubiquitous functional groups such as alcohols, carboxylic acids, amines and amides, which serve as central “actors” in most organic reactions, sulfamates, phosphoramidates and di-tert-butyl silanols have historically been viewed as “extras."

Largely considered functional group curiosities rather than launchpoints of vital reactivity, the chemistry of these moieties is underdeveloped. Our research program has uncovered facets of reactivity of each of these functional groups, and we are optimistic that the chemistry of these fascinating molecules can be developed into general transformations useful for chemists across multiple disciplines. In the ensuing sections, I will describe our efforts to develop new reactions with these “unusual” functional groups, namely sulfamates, phosphoramidates, and di-tert-butyl silanols.

Compared to ubiquitous functional groups such as alcohols, carboxylic acids, amines and amides, which serve as central “actors” in most organic reactions, sulfamates, phosphoramidates and di-tert-butyl silanols have historically been viewed as “extras."

Largely considered functional group curiosities rather than launchpoints of vital reactivity, the chemistry of these moieties is underdeveloped. Our research program has uncovered facets of reactivity of each of these functional groups, and we are optimistic that the chemistry of these fascinating molecules can be developed into general transformations useful for chemists across multiple disciplines. In the ensuing sections, I will describe our efforts to develop new reactions with these “unusual” functional groups, namely sulfamates, phosphoramidates, and di-tert-butyl silanols.