Abstract 2341 Learning from Nature: strategies for drugging dynamic nuclear proteins

Conformationally dynamic proteins are at the heart of most cellular machines and frequently dysregulated in disease. Unfortunately, they are often considered 'undruggable' as they are not amenable to targeting by standard drug discovery methodologies. This is particularly true for transcriptional coactivators and activators, proteins that are linked to many disease states yet are have few probes or drugs that engage them. Using transient kinetic studies of activator-coactivator complexes coupled with structural studies, we found that unstructured loop regions adjacent to canonical binding sites within coactivators proteins play a central role in the specific recognition of transcriptional activator binding partners and in allosteric communication between binding sites. Through screening we have found that these sites are amenable to small-molecule targeting and have identified first in-class inhibitors for challenging targets such as Med25. Further, we have developed a screening workflow that enables rapid discovery of submicromolar inhibitors for several transcriptional coactivators and other dynamic nuclear proteins. Mapp is grateful for financial support from the National Institutes of Health (GM136356) for this work.