High throughput screening to discover inhibitors for IP6K1 as a potential treatment for psychiatric disorders

Lieber Institute, Inc., Baltimore MD

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Abstract

Abstract Bipolar disorder (BD) and schizophrenia (SCZ) are devastating psychiatric disorders with huge unmet needs for effective and safe treatment. Aberrant glycogen synthase kinase-3 (GSK3) activity has been linked to BD and SCZ. GSK3 is involved in the mechanism of action for certain psychoactive drugs including antipsychotics as well as lithium and other mood stabilizers. Direct inhibition of (GSK3) activity has been shown to be effective in modulating behaviors in several animal models related to psychiatric disorders. However, since GSK3 is essential for many aspects of cellular function, undesired toxicological effects have been observed with several GSK3 inhibitors. There is strong evidence leading us to the hypothesis that that up-regulating AKT activity through inhibition of IP6K1 may improve the sensitivity of BD and SCZ patients to therapies that influence GSK3, including lithium and antipsychotic drugs. In addition, it may lower the therapeutic dose of these agents thereby increasing their therapeutic indices. To test our hypothesis, we propose to screen for an IP6K1 inhibitor using a high throughput screening method we developed to screen the NCATS Chemical Genomics Center (NCGC) chemical library. We will then confirm the inhibitors and prioritize them based on cheminformatics analysis, enzymatic assays, cell based assays, specificity and selectivity. We will also study their mechanism of action. We expect this project will help us identify new leads that could serve as starting points for testing our hypothesis and a future drug discovery campaign towards novel therapeutics for psychiatric disorders.