Drug discovery strategy for TAK-418, a specific inhibitor of LSD1 enzyme activity, as a novel therapy for autism.

The pathophysiology of neurodevelopmental disorders is associated with multiple genetic and environmental risk factors. Epigenetics, owing to its potential to recover global gene expression changes associated with disease conditions, is a crucial target to address neurodevelopmental disorders influenced by genetic and environmental factors. Here, we discuss the discovery of selective inhibitors of lysine-specific demethylase 1 (LSD1) enzyme activity and their therapeutic potential for neurodevelopmental disorders through epigenetic regulation in the brain. Conventional LSD1 inhibitors not only inhibit LSD1 enzymatic activity but also interfere with LSD1-cofactor complex formation, thus leading to hematological side effects. Notably, investigations on the structure-activity relationship have revealed (aminocyclopropyl)benzamide and (aminocyclopropyl)thiophene carboxamide derivatives as novel series of LSD1 inhibitors with fewer hematological side effects. Subsequently, we discovered T-448 and TAK-418 (clinical candidate) that selectively and potently inhibit LSD1 enzymatic activity without disrupting the LSD1-cofactor complex, resulting in potent epigenetic modulation without significant hematological toxicity risks in rodents. T-448 and TAK-418, at doses that achieved almost complete LSD1 occupancy in the brain, improved behavioral abnormalities in multiple rodent models of neurodevelopmental disorders. Furthermore, comprehensive RNA expression analyses revealed that, although gene expression abnormalities exhibited limited commonality across disease models, TAK-418 normalized each aberrant gene expression pattern in these rodent models. A positron emission tomography tracer was discovered to potentially measure the occupancy of TAK-418 at the LSD1 active site in the brain to improve the translatability of its preclinical efficacy to therapeutic effects in humans. TAK-418-type LSD1 inhibitors may offer novel treatment options for neurodevelopmental disorders.