Novel and functionally selective 5-HT2C receptor agonist for treating Alcohol Use Disorder

PROJECT SUMMARY The goal of this project is to confirm and extend the drug candidacy of KB128 as a novel therapeutic medication for alcohol use disorder (AUD), a common and devastating illness with inadequate treatment options. Current drugs approved by the FDA for AUD are characterized by low efficacy and stereotypical side effects that reduce treatment adherence. The 5-HT2C receptor is a validated therapeutic drug target for AUD. However, previous attempts to design selective 5-HT2C receptor ligands have been plagued by undesirable off-target effects, includ- ing aberrant activation of 5-HT2A (hallucinations) and 5-HT2B (valvulopathy), or a lack functional selectivity by activating both Gq signaling (mediating the putative therapeutic effect) and β-arrestin signaling (leading to recep- tor internalization and attenuation of signal). Production and commercialization of a safe and selective 5-HT2C receptor agonist with functional Gq bias, negligible β-arrestin recruitment, and no hallucinogenic or cardiotoxic liabilities associated with 5-HT2A and 5-HT2B receptor activation would be a market-changing differentiator; no 5- HT2C agonist commercialized thus far exhibits this profile. Küleon, LLC has developed a proprietary platform of molecular scaffolds with unique receptor docking profiles. Our preliminary studies demonstrate lead candidate KB128 exhibits high selectivity for 5-HT2C, Gq-mediated signaling bias with minimal β-arrestin recruitment, favor- able metabolic profile, no hallucinogenic or cardiotoxic liabilities, and efficacy in a pilot AUD study in rodents. Our Phase I objective for KB128 is to demonstrate preclinical efficacy in more extensive AUD behavioral models, favorable pharmacokinetics, and no off-target toxicity. We will accomplish this in the following two Aims. (1) Demonstrate KB128’s ability to attenuate alcohol self-administration and stress-induced relapse in validated ro- dent models. 5-HT2C receptor signaling has been implicated in the development and maintenance of AUD, and prior studies have shown that 5-HT2C receptor agonists can significantly decrease alcohol consumption in both rodents and humans. Stress-induced relapse as a secondary readout of a self-administration study can provide an invaluable model for testing a drug’s ability to attenuate stress-induced reinstatement of alcohol-seeking be- havior in both male and female rodents. (2) Demonstrate favorable pharmacokinetics and a lack of cardiotoxicity and drug-drug interactions (DDIs) for KB128. KB128 will be tested in a variety of ADMET studies in at least 5 species, including plasma stability and plasma protein binding for all species tested. An in vitro cardiomyocyte assay will be conducted to measure changes in intracellular Ca++ transients; success will be defined by <15% change in mean peak rate, peak spacing, and calcium transient duration. CYP450 induction, CYP450 reaction phenotyping and CYP450 time-dependent and direct/reversible inhibition assays will be conducted to confirm that KB128 does not exhibit potential cytotoxicity and negative DDIs. Our research team combines expertise in small molecule drug development, in vivo pharmacology, preclinical biological testing in rodent AUD models, patent procurement, and commercialization.