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

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.

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Journal
Journal of Biological Chemistry
Published
2025-12-22
DOI
https://doi.org/10.1016/j.jbc.2025.111080
Primary Topic
Neuroscience and Neuropharmacology Research
Type
article
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article

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

H Chen, Corey P. St. Romain, Earnest P. Chen, Yun Young Yim et al.
Journal of Biological Chemistry
Neuroscience and Neuropharmacology Research
article

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

H Chen, Corey P. St. Romain, Earnest P. Chen, Yun Young Yim, Brandon W. Hughes, Alfred J. Robison, Reid T. Powell, Gabby Rudenko, Galina V. Aglyamova, Mischa Machius, Jeannie Chin, Y. Li, Shanghua Fan, Clifford Stephan, Gabriel S. Stephens, Solange Tofani, Ashwani Kumar, Molly Estill, Samantha J. Kruzshak, Corrine Brener, Jianping Chen, Sean McNeme, Jia Zhou, Stephen J. Haggarty, Nadeen Takatka, Nghi D. Nguyen, Wen-Ning Zhao, Anil Kumar, Eric J. Nestler
article en

Abstract

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.

Journal of Biological ChemistryVol. 302(2)
Allen Institute for Brain Science (US), Texas A&M University System (US), Baylor College of Medicine (US), Massachusetts General Hospital (US), The University of Texas Medical Branch at Galveston (US), Michigan State University (US)
Good health and well-being
Openalex Percentile: Top 38%
Neuroscience and Neuropharmacology Research
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