Orally available allosteric inhibitor of protein sumoylation

PROJECT SUMMARY ABSTRACT Extensive studies have indicated that post translational modification by the small ubiquitin like modifierSUMOfamily of proteins is a promising cancer therapeutic targetc Myc dependent cancersincluding colorectal cancerrepresent major unmet medical needs that currently lack targeted therapyRecent scientific advances revealed that thisundruggableoncogene critically depends on SUMOylationFurthermoreinhibiting SUMOylation can potentially activate anti tumor immune responsesGenome wide gene expression analysis of patient tumor tissues in comparison with normal tissues demonstrated that the SUMO activating enzymeEis the most overexpressed SUMOylation related protein in colorectal cancers tissuesSUMO Eoverexpression is also associated with cancer cell stemness and poor patient survivalThis evidence makes SUMO Ean attractive cancer therapeutic targetThereforeour objective in this proposal to develop highly selectivepotentorally available and in vivo efficacious SUMO Einhibitors as targeted therapies for colorectal cancers that overexpress c MycUsing a fragment based approach designed to target a newly discovered SUMO Eallosteric binding sitewe identified a class of potent and specific SUMO Einhibitors suitable for development into orally available drugswhich could represent a new class of therapeutic agentsIn the proposed studywe will conduct lead optimization of these compounds and validate the resulting candidates in assays using colorectal cancer cell linesTo identify efficacious candidates with favorable bioavailability and pharmacokinetic propertieswe will perform bioavailabilitypharmacokineticand toxicity studies in mouse modelsWe expect to obtain a SUMO Einhibitor that is orally available and suitably potent in mouse models for further developmentIn addition to colorectal cancerwhich is the focus of this proposalinhibiting SUMOylation will likely inhibit other c Myc dependent cancers and potentially induce anti tumor immune responseThuswe expect the potent SUMO Einhibitors we develop in the proposed study to have a major impact on cancer research and targeted therapy PROJECT NARRATIVE Our goal is to develop orally available and efficacious SUMO Einhibitors as targeted therapies for colorectal cancers that overexpress c Myca major oncogene that is considered undruggable