The AP1 transcription factor ΔFOSB can be pharmacologically targeted through a novel druggable groove located outside the DNA-binding cleft, where sulfonic acid-containing small molecules bind via an induced-fit mechanism to reorient DNA-binding residues, resulting in approximately 60% reduction in genomic ΔFOSB occupancy in vivo as demonstrated by CUT&RUN-sequencing in mouse brain.

ΔFOSB, a member of the AP1 family of transcription factors, mediates long-term neuroadaptations underlying drug addiction, seizure-related cognitive decline, dyskinesias, and several other chronic conditions. AP1 transcription factors are notoriously difficult to modulate pharmacologically due to the absence of well-defined binding pockets. Here, we identify a novel site on ΔFOSB, located outside the DNA-binding cleft, that accommodates small molecules. We show that sulfonic acid-containing compounds bind to this site via an induced-fit mechanism, reorienting side chains critical for DNA binding, and that they may hinder the ΔFOSB bZIP α-helix from binding to the major groove of DNA. In vivo, direct administration of one such compound, JPC0661, into the brain reduces ΔFOSB occupancy at genomic AP1 consensus sites by approximately 60% as determined by CUT&RUN-sequencing. These findings suggest that DNA binding and release by AP1 transcription factors can be controlled via small molecules that dock into a novel site that falls outside of the DNA-binding cleft. Minimal sequence conservation across 29 bZIP domain-containing transcription factors in this druggable groove suggests that it can be exploited to develop AP1-subunit-selective compounds. Our studies thus reveal a novel strategy to design small-molecule inhibitors of ΔFOSB and other members of the bZIP transcription factor family.