bioRxiv2025
{Delta}FOSB, an unusually stable member of the AP1 family of transcription factors, mediates long-term maladaptations that 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 {Delta}FOSB to DNA in vitro in cell-based assays, and one such compound, JPC0661, disrupts {Delta}FOSB binding to genomic DNA in vivo in mouse brain with partial efficiency. JPC0661 binds to a groove outside of the DNA-binding cleft of the {Delta}FOSB/JUND bZIP heterodimer in the co-crystal structure. Here, we generated a panel of analogs of JPC0661 with the goal of establishing structure-activity relationships and improving its in vivo efficacy by replacing the amino-pyrazolone cap moiety with various substituents. We show that one such analog, YL0441, disrupts the binding of {Delta}FOSB to DNA in vitro and in vivo, and suppresses {Delta}FOSB-function in cell-based assays. Importantly, infusion of YL0441 into the hippocampus of APP mice (a mouse model for Alzheimers disease) leads to virtually complete loss of {Delta}FOSB bound to genomic DNA by CUT&RUN sequencing. Our findings corroborate that DNA binding/release of AP1 transcription factors can be controlled via small molecules, 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 highly efficacious inhibitor of {Delta}FOSB function in vivo. These findings define a strategy to design small-molecule inhibitors for other AP1- and AP1-related transcription factors. IN BRIEFWe demonstrate the creation of a highly effective inhibitor, YL0441, of {Delta}FOSB, an AP1 transcription factor, which decreases the number of {Delta}FOSB-bound sites to genomic DNA by [~]94% upon in vivo infusion to the hippocampus of APP mice, a mouse model for Alzheimers disease. This work generates a highly novel probe compound to assess the therapeutic value of {Delta}FOSB in vivo, a transcription factor with a critical role in mediating long-term changes in gene expression in several neuropsychiatric disorders in addition to Alzheimers disease, including drug addiction, seizure-related cognitive decline, and dyskinesias.