Novel SUMO Activators for the Treatment of Duchenne Muscular Dystrophy-Associated Heart Failure

PROJECT SUMMARY Our objective is to develop a small molecule therapy for the treatment of heart disease associated with Duchenne Muscular DystrophyDMDa disease that occurs inout of everymale birthsand for which there is no cure or long term effective treatmentHeart failureHFis a contributing cause of mortality among persons afflicted with DMDA key abnormality in HF is defective handling of calcium that has been partially related to abnormal sarcoplasmic reticulumSRfunction in cardiac myocytesReduced expression and altered activity of the cardiac SR CaATPaseSERCA ahave been found in human and animal models of HFOur group has described a role for the small ubiquitin like modifier typeSUMOas a regulator of SERCA a and has shown that gene transfer of SUMOin rodents and large animal models of HF restores cardiac functionThrough an extensive small molecule screenwe have identified and characterized a small moleculeNwhich increases SUMOylation of SERCA aThis compound directly activates the SUMO activating enzymeEligaseand triggers intrinsic SUMOylation of SERCA aWe identified a unique binding pocket on SUMO Ethat is responsible for Ns effectsWe have completed pharmacokineticstoxicityand off target studies on this compound along with detailed biological activities in vivoIn this proposalwe provide preliminary evidence that SUMOpathway was impaired in mouse DMD heartswhich was accompanied by SERCA a dysfunctionand for the feasibility of our novel therapy in DMDThe key objective of this Phase I SBIR proposal is to identify candidate hits small molecule activators of SERCA a SUMOylation from a set of new scaffoldsWe have used computational modeling to perform in silico screening of the validated Eenzyme pocket to identify new scaffolds for further evaluationIn our first aim we propose synthesizingand testing the efficacy and ADME PK of our novel chemical classes of small molecule activatorsi edifferent new scaffoldsto tailor an improved PK profile than Nand increased half lifeThe SAR studytogether with the SUMO Eactivity assaywill identify and prioritize hits to leadsIn our second aimwe will determine the potencythe safetyand the molecular mechanism of action of our three selected lead candidatesA combination of SERCA a SUMOylation assays and cardiomyocytes experiments will define mechanisms of actionand together with the PK studies will identify lead compounds for future developmentFinallywe will test the efficacy of our lead therapeutic in a mouse model of DMDTesting oral doses of small molecule activators of SUMOylation in established DMD models will allow us to show improvement in cardiac function and cardiac pathologyThe completion of these studies will guide us towards a path for future clinical application in Phase II SBIR plan PROJECT NARRATIVE Duchenne Muscular DystrophyDMDa degenerative and commonly terminal disease involving the cardiac and skeletal musclesaffects thousands of young boys across the United StatesThe majority of patients with DMD have cardiac involvement that manifests into heart failureOur long term goal at SUMOCOR LLC is to develop a novel efficacious drug to treat DMD related heart disease