Elucidation and characterisation of high throughput degrader screening outputs

Abstract

Targeted protein degradation is
an important function of the cellular machinery that is gaining momentum as an
exploitable strategy for drug discovery. Molecules that are able to induce
proximity between intractable therapeutic targets and the proteasomal
degradation machinery are slowly changing the druggable target landscape. Having
the ability to detect and understand the mechanism of action of hit molecules
identified from a direct screen for degraders is becoming increasingly
attractive. We have established a post-HTS cascade of experiments including
cell-based assays as well as orthogonal triage steps to provide annotation on
the selectivity and mechanism of action for primary screening hits against a
high value oncology target. We will describe our current position on the analysis
of these novel outputs and highlight challenges encountered.