Grasilda Zenkeviciute, Proxygen, Wien

Targeted protein degradation (TPD) is emerging as an important approach in pharmaceutical research and holds potential for changing the scope of drugs by enabling the targeting of proteins previously deemed undruggable. Molecular Glue Degraders (MGDs) induce a ternary complex through protein–protein interactions between a ubiquitin ligase and a target protein, thereby resulting in ubiquitination and subsequent degradation of the target protein.

Proxygen’s rational molecular glue discovery platform enables the identification and optimization of novel MGDs at scale. Using this platform, a novel class of MGDs were identified. Chemical optimization of structurally distinct hits and characterization by cellular and biophysical methods revealed two distinct mechanisms of action. In particular, it emerged how modulation of assembly and dissociation dynamics of the ternary complex can affect the target degradation. This leads to a better understanding of how to rationally modulate degradation kinetics, maximal degradation levels (Dmax), and potency (DC50) to guide the design of MGDs towards the optimal drug profile.