Preclinical development of a precision therapy for a monogenic mental health disorder - PROJECT SUMMARY In this project, we propose to develop primary and secondary lead small molecules into preclinical drug candidates for a precision SYNGAP1-DEE therapy. This research is consistent with the mission of NIMH because this genetic disorder impacts mental health and behavior through impairments in intellectual and social adaptive functioning. Pathogenic SYNGAP1 variants may explain up to 1% of non-X-linked neurodevelopmental disorder cases and the estimated prevalence of these mutations is similar to that of Fragile X syndrome, or 1-4/10,000 live births. Most, if not all, SYNGAP1-DEE cases are caused by variants that lead to genetic haploinsufficiency (i.e. 50% of normal protein levels). Therefore, a rational strategy to treat these patients is to develop precision-based approaches that “boost” low SynGAP protein expression in affected brain cells. In prior NIMH funded research, we developed a novel phenotypic screening platform, NDD-ChemScreen, which can detect chemical and biological agents that raise target gene/protein expression in haploinsufficient neurons. This platform was used to discover lead small molecule compounds that substantially raise SynGAP protein. Small molecules have distinct advantages compared to other approaches for genetic disorders that impact central nervous system function. They can regulate disease- driving biology, be delivered orally and still concentrate in brain tissue, and dosing can be easily adjusted to fit individual patient needs and rapidly respond to adverse effects. While these compounds currently work well in vitro, here we will optimize through established preclinical drug development workflows. This U01 research project has three specific aims. Specific Aim 1 will focus on optimizing the primary lead, SR-1815, through medicinal chemistry. We will perform extensive SAR on SR-1815 to optimize potency, efficacy, brain penetrance, solubility, and other drug-like properties (e.g., microsomal stability, CYP inhibition) to reach a primary optimized lead. Specific Aim 2 will focus on identifying and optimizing a secondary lead series for SYNGAP1-DEE with a chemical scaffold that is distinct from the primary lead. This will de-risk the overall development of small molecules for SYNGAP1-DEE by mitigating unforeseen dead-ends that can occur during development of any given chemical scaffold. Specific Aim 3 will focus on scale-up and early-stage preclinical development of one optimized lead compound (i.e. the best of the primary or secondary optimized leads). This aim will including in vitro safety pharmacology testing and end with non- GLP dose-range finding studies in two species to determine tolerability and safety. The end result of this project will be a preclinical candidate ready for IND-enabling studies, which will be a launch pad for subsequent clinical research projects aimed at improving the quality of life for patients diagnosed with SYNGAP1-DEE.
