DNA-encoded chemical library screening for glue discovery for oncology targets

There is considerable interest in the discovery of novel molecular glues that induce proximity between oncology targets and their modulators. Induced proximity can be used to degrade proteins by a range of mechanisms, including ubiquitination and trafficking to the proteasome. DNA-Encoded Chemical Library screening can readily be adapted to the discovery of glues, and we will describe case studies that exemplify how carefully designed screening campaigns with highly diverse encoded compound libraries can identify small molecules capable of inducing proximity. Case studies will include a small molecule discovered in a DEL screen against ATAD2 that is able to inappropriately dimerize ATAD2 thereby reducing its ability to bind to acetylated histones and an activator of the integrated stress response pathway that only binds to the eIF2b complex, not its isolated components, thereby stabilizing it.