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Drug Discovery for Multiple Hereditary Exostoses

Multiple hereditary exostoses (MHE) is an autosomal dominant disorder that results from heterozygous loss‐of‐function genetic mutations in exostosin 1 (EXT1) or exostosin 2 (EXT2). One in 50,000 children worldwide are affected by this relatively rare pediatric disease, which is characterized by osteochondromas that form next to the growth plates of skeletal elements. EXT1 and EXT2 encode the copolymerase responsible for biosynthesis of the backbone of heparan sulfate (HS), a cell surface polysaccharide. Heterozygous mutations in EXT1 or EXT2 lead to shortened HS chains in plasma and various tissues. Currently, there are no approved therapies for this disease; therefore, there is much interest in preventing and/or slowing the growth of exostoses through the development of small molecules that enhance HS levels on the cell surface. In this study, a high‐throughput phenotypic screen was developed to discover potential small molecule drug candidates that augment HS expression in mammalian cells. Screening of a compound library of ~57,000 molecules resulted in the discovery of several N‐aryl‐2‐aminothiazoles that displayed favorable “drug‐like” physicochemical properties, exhibited minimal cytotoxicity, and enhanced HS expression up to 3‐fold on the cell surface. Preliminary studies of structure‐activity relationships identified active analogs of the primary hit and key physicochemical properties required for their biological activity. Ongoing studies aim to expand the SAR studies, identification of a preferred candidate for in vivo studies, and finding the biological target for these compounds. Overall, these studies provide a promising new avenue for the development of novel therapies for MHE and other disorders involving glycosaminoglycan deficiencies.