9oc3

Publication Abstract from PubMed

DeltaFOSB, a member of the AP-1 family of transcription factors, mediates long-term neuroadaptations underlying drug addiction, seizure-related cognitive decline, dyskinesias, and several other chronic conditions. AP-1 transcription factors are notoriously difficult to modulate pharmacologically due to the absence of well-defined binding pockets. Here, we identify a novel site on DeltaFOSB, 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 DeltaFOSB bZIP alpha-helix from binding to the major groove of DNA. In vivo, direct administration of one such compound, JPC0661, into the brain reduces DeltaFOSB 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 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 AP-1-subunit-selective compounds. Our studies thus reveal a novel strategy to design small-molecule inhibitors of DeltaFOSB and other members of the bZIP transcription factor family.

Discovery of Small Molecules and a Druggable Groove That Regulate DNA Binding and Release of the AP-1 Transcription Factor DeltaFOSB.,McNeme S, Yim YY, Kumar A, Li Y, Hughes B, St Romain CP, Aglyamova G, Chen J, Nguyen ND, Fan S, Stephens GS, Zhao WN, Kruzshak S, Estill M, Brener C, Tofani S, Kumar A, Chen EP, Takatka N, Robison AJ, Chen H, Powell RT, Haggarty SJ, Stephan C, Nestler EJ, Chin J, Machius M, Zhou J, Rudenko G J Biol Chem. 2025 Dec 22:111080. doi: 10.1016/j.jbc.2025.111080. PMID:41443415^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.