Optimization of an integrin enhancing molecule for the treatment of Duchenne muscular dystrophy

DESCRIPTION provided by applicant Duchenne muscular dystrophy is caused by mutations in the dystrophin gene resulting in the loss of the dystrophin glycoprotein complex in skeletal muscle Loss of dystrophin results in reduced sarcolemmal integrity progressive muscle damage and compromised muscle function There is currently no cure and limited treatment options for DMD and all affected children will die from this genetic disease unless new treatments are discovered soon The integrin is major laminin receptor which can act as a surrogate for the dystrophin complex in skeletal muscle Studies have demonstrated that enhanced transgenic expression of the integrin in skeletal muscle can improve muscle strength function and longevity of mouse models of DMD Together these studies indicate that drugs that target an increase integrin in skeletal muscle may serve as novel therapies for DMD The Burkin laboratory has developed and used a muscle cell based assay to identify small molecules that increase the integrin in skeletal muscle Strykagen Corp has the option to license Stryka the top andquot hitandquot compound identified from this screen In this Phase I STTR application we will screen Stryka compound analogs using the muscle cell based assay and develop structure activity relationships SAR perform medicinal chemistry and identify lead compounds with optimal activity that target the integrin in mouse and human myogenic cells for further development Second we will confirm on target and off target activity of each lead compound in human DMD myogenic cells This proposal will translate exciting studies in transgenic mice into the development of a new line of integrin targeted therapeutics for the treatment of DMD PUBLIC HEALTH RELEVANCE Duchenne Muscular Dystrophy DMD is a fatal muscular disease that currently has no cure and limited treatment options Several studies have demonstrated that the integrin is a major modifier of disease progression in DMD and target for drug based therapeutics In collaboration with Dean Burkin at the University of Nevada School of Medicine Strykagen Corp has the option to the exclusive license for a novel integrin enhancing small molecule Stryka which has significant potential in the treatment of DMD This study aims to identify a potent lead compound based on the Stryka platform and confirm on target activity in DMD myogenic cells