Efficient In Vivo Pharmacological Inhibition of ΔFOSB, an AP-1 Transcription Factor, in the Brain

ΔFOSB, an unusually stable member of the AP-1 family of transcription factors, mediates long-term maladaptations that play a key role in the pathogenesis of drug addiction, cognitive decline, dyskinesia, and several Other chronic neurological and psychiatric conditions. We have recently identified that 2-phenoxybenzenesulfonic acid-containing compounds disrupt the binding of ΔFOSB to DNA in vitro in cell-based assays, and one such compound, JPC0661, disrupts ΔFOSB binding to genomic DNA in vivo in the mouse brain with partial efficiency. JPC0661 binds to a groove outside of the DNA-binding cleft of the ΔFOSB/JUND bZIP heterodimer in a cocrystal structure. Here, we generated a panel of analogs of JPC0661 to establish structure-activity relationships and improve its in vivo efficacy by replacing its amino-pyrazolone cap moiety with various substituents. We show that one such analog, YL0441, disrupts the binding of ΔFOSB to DNA in vitro and in vivo and suppresses ΔFOSB function in cell-based assays. Importantly, infusion of YL0441 into the hippocampus of APP mice (a mouse model for Alzheimer's disease neuropathology) leads to virtually complete loss of ΔFOSB bound to genomic DNA as detected by CUT&RUN Sequencing. Our findings corroborate that the binding/release of AP1 transcription factors to DNA can be controlled via small molecules in vivo, even by analogs of a compound that binds to a groove outside of the DNA-binding cleft, and that our lead can be optimized via medicinal chemistry to yield a much more efficacious inhibitor of ΔFOSB function in vivo. These findings define a strategy to design small-molecule inhibitors for Other AP-1 and AP-1-related transcription factors, in particular, those involved in neuropsychiatric and neurological disorders.

AP-1 transcription factor; Alzheimer’s disease; CUT&RUN; DNA−protein interactions; bZIP domain; drug addiction; in vivo pharmacology; small-molecule inhibitors; substance use disorder; transcriptional reprogramming; ΔFOSB.