Discovery of small molecules and a druggable groove that regulate DNA binding and release of the AP-1 transcription...

ΔFOSB, a member of the activator protein 1 (AP-1) family of transcription factors (TFs), mediates long-term neuroadaptations underlying drug addiction, seizure-related cognitive decline, dyskinesias, and several other chronic conditions. AP-1 TFs are notoriously difficult to modulate pharmacologically because of the absence of well-defined binding pockets. Here, we identify a novel site on ΔFOSB, located outside the DNA-binding cleft, which 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 basic leucine zipper (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 AP-1 consensus sites by approximately 60% as determined by CUT&RUN sequencing. These findings suggest that DNA binding and release by AP-1 TFs can be controlled via small molecules that dock into a novel site that falls outside the DNA-binding cleft. Minimal sequence conservation across 29 bZIP domain-containing TFs in this druggable groove suggests that it can be exploited to develop AP-1 subunit-selective compounds. Our studies thus reveal a novel strategy to design small-molecule inhibitors of ΔFOSB and other members of the bZIP TF family.