Developing a novel epigenetic regulator as a treatment for cocaine use disorder

Developing a novel epigenetic regulator as a treatment for cocaine use disorder Project Summary/Abstract Cocaine use disorder (CUD) is a major public health problem that is associated with substantial morbidity and mortality. Treatment for CUD primarily consists of behavioral interventions including contingency management, cognitive behavioral therapy, or therapeutic communities. However, these approaches result in a substantial relapse rate in those seeking treatment, and despite efforts to develop pharmacological agents, no medications have been proven safe and effective for the treatment of CUD. One reason that people with CUD have difficult quitting and remaining abstinent is the intense drug-related contextual memory that links drug use to euphoria-like feelings. We have recently identified a novel mechanism of that promotes neuronal plasticity and memory consolidation/reconsolidation via ACSS2, a metabolic enzyme that regulates histone acetylation and Immediate Early gene expression involved in memory formation and retrieval. We hypothesize that small molecule inhibitors of ACSS2 will selectively disrupt drug and cue-related memory reconsolidation, leading to diminished drug craving, thereby enabling preventing relapse in people with CUD. Using a commercially available ACSS2i (ADG-205), we have demonstrated that acute inhibition of ACSS2 can decrease relapse behavior in several pre-clinical models of substance abuse, including nicotine, alcohol, opioid and cocaine. While ADG-205 has proven efficacious, we cannot patent the molecule and we have observed some less than ideal pharmacological properties. Through medicinal chemistry efforts, we generated 55 new compounds. One compound in particular, EPV, exhibits a novel scaffold, with improved efficacy and brain bioavailability. The aim of this application is to establish EPV as a viable new generation of ACSS2 inhibitor through 2 ams. Aim 1 will assess pharmacological parameters such as selectivity, functional efficacy on histone acetylation and gene regulation, ADME properties and basic pharmacokinetics. Aim 2 will focus on testing our novel scaffold in a pre-clinical model of cocaine use called intravenous self-administration. Additionally, we will confirm that EPV treatment does not affect learning and non-targeted memories. These studies will yield a novel lead candidate molecule with improved pharmacological properties, which will lead to a new program of medicinal chemistry to develop new drug candidates. Overall, our program proposes an entirely new mechanism of action for treating cocaine addiction. Significant strengths of the application include the novelty of the proposed target, required in vitro and in vivo assays already in place, and a novel chemical scaffold to initiate drug development.