Development of an oral drug targeting SUMOylation

c Mycand KRas dependent cancerssuch as colorectal cancerrepresent major unmet medical
needs that currently lack targeted therapyRecent scientific advances revealed that theseundruggableoncogenes critically depend on post translational modification with the small
ubiquitin like modifierSUMOfamily of proteinsand inhibiting SUMOylation inhibits c Myc and
KRasFurthermoreSUMOylation inhibition can activate anti tumor immune responsesGenomewide gene expression analysis has 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 targetThereforewe propose to develop highly selectivepotentand orally available SUMO Einhibitors as targeted therapies for colorectal cancerUsing a
high throughput screening campaignwe have identified a class of potent and specific SUMO Einhibitors suitable for development into orally available drugswhich could represent a new class of
therapeutic agentsWe will conduct lead optimization of these compounds and validate the
resulting candidates in cellular assays of colorectal cancerfollowed by pharmacokinetic and
toxicity studiesIn addition to colorectal cancerwhich is the focus of our proposalinhibiting
SUMOylation will likely inhibit other c Myc and KRas dependent cancersThusthe potent SUMO
Einhibitors developed in the proposed studies are expected to have a major impact on cancer
research and targeted therapy We propose to develop an orally available SUMO Einhibitor for cancer therapy