Advancing Nr4a1 as a novel target in cocaine use disorder.

PROJECT SUMMARY National rates of cocaine use are rising, with approximately 2.2 million persons with a substance use disorder and 1 million individuals afflicted with addiction reported in 2019. Despite these alarming statistics, no medications have been approved for cocaine abuse. The current standard in treatment is psychosocial intervention, which is burdened by high dropout rates. Using fundamental approaches, we recently validated Nr4a1 as a novel target to suppress cocaine reward behavior in mice. We discovered that Nr4a1 engagement as a measure of downstream effects such that both CRISPR and small molecule activation of Nr4a1 suppress cocaine reward behavior in mice. The small molecule, Cytosporone B (CsnB), is a naturally occurring Nr4a1 agonist with strong affinity for Nr4a1 and its ligand-binding domain. We recently established that (1) cocaine increases Nr4a1 in mouse striatum and (2) Nr4a1 activation by CRISPRa (FIG 1) or systemic administration CsnB suppresses mouse cocaine reward behavior. This STTR Phase I proposal enters at the lead identification (LI) stage and proposes development of Nr4a1- targeted therapy for cocaine use disorder. We have completed the initial drug discovery and development (DDD) milestones of target identification (TI) and target validation (TV) through prior publication and completion of NIDA SEP III: Step Up for Substance Use Disorders (SUD): A Drug Target Initiative for Scientists Engaged in Fundamental Research (U18). We showed that modulation of Nr4a1 has the desired effect in models of cocaine use disorder, demonstrated proof of target validation, developed an Nr4a1 Target Dossier, and defined a Target Product Profile (TPP). This STTR Phase I Proposal establishes milestones towards the successful filing of a commercially-viable IND application, including, (1) Lead Identification (LI): synthesis and screening of CsnB derivatives that activate human/mouse NR4A1/Nr4a1 and (2) Lead Optimization (LO): characterization of lead compound(s) using direct binding assays, synthetic feasibility, and pharmacokinetics. Through this proposal we will identify a commercially viable, NR4A1-activator lead compound that has the optimal attributes for preclinical testing and IND application initiation. These results are expected to have a positive impact because there is currently no approved medication for cocaine use disorder and tens of thousands of overdose deaths each year. Importantly, NR4A1 is a first-in-class therapeutic target in cocaine use disorder, harnessing the power of gene regulatory mechanisms to reverse the deleterious effects of chronic cocaine exposure.