Efficient in vivo pharmacological inhibition of ∆FOSB with YL-0441 in brain

ΔFOSB, an unusually stable member of the AP-1family of transcription factors, mediates long-term maladaptationsthat play a key role in the pathogenesis of drug addiction, cognitive decline, dyskinesias, 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 vitroin cell-based assays. We show that one such analog, YL0441, disrupts the binding of ΔFOSB to DNA in vitroand 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 diseaseneuropathology) 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 moleculesin 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 moreefficacious inhibitor of ΔFOSB function in vivo. These findings define a strategy to design small-molecule inhibitors for other AP-1and AP-1-related transcription factors, in particular, those involved in neuropsychiatric and neurological disorders.