Abstract

Small molecules that induce protein degradation through ligase-mediated ubiquitination have shown considerable promise as a new pharmacological modality. We and others have demonstrated that efficacious degradation of kinases and other targets can be achieved in vitro and in vivo, however, many targets remain recalcitrant to degradation. In this presentation, I will discuss how we took advantage of two library design approaches to build family-centric degrader libraries targeted towards protein kinases and zinc-dependent HDACs. We then utilized high throughput chemical-proteomics approaches to map protein degradability identifying hundreds of proteins as degradable targets. Using the accumulated data we evaluated the contributions that chemical and cellular variables have on TPD efficacy and selectivity and found that they play a surprisingly inconsistent role in degradation success. We demonstrate that the accumulation of large unbiased datasets such as this can serve as a rich source of small molecule tools for studying biology of different proteins, can enable mapping of tractable targets and can provide chemical lead molecules for many new target proteins. We are now offering free degrader target profiling to the public to expand the degradable proteome map and accelerate the development of degraders as novel chemical probes for various therapeutic targets.