Discovery of Small Molecules and a Druggable Groove That Regulate DNA Binding and Release of the AP-1 Transcription Factor ΔFOSB

  • J Biol Chem. 2025 Dec 22:111080. doi: 10.1016/j.jbc.2025.111080.
Sean McNeme  1 ,  Yun Young Yim  2 ,  Ashwani Kumar  1 ,  Yi Li  1 ,  Brandon Hughes  2 ,  Corey Peyton St Romain  3 ,  Galina Aglyamova  1 ,  Jianping Chen  1 ,  Nghi D Nguyen  4 ,  Shanghua Fan  1 ,  Gabriel S Stephens  3 ,  Wen-Ning Zhao  5 ,  Samantha Kruzshak  5 ,  Molly Estill  2 ,  Corrine Brener  2 ,  Solange Tofani  2 ,  Anil Kumar  1 ,  Earnest P Chen  2 ,  Nadeen Takatka  1 ,  Alfred J Robison  6 ,  Haiying Chen  1 ,  Reid T Powell  4 ,  Stephen J Haggarty  5 ,  Clifford Stephan  4 ,  Eric J Nestler  2 ,  Jeannie Chin  3 ,  Mischa Machius  1 ,  Jia Zhou  1 ,  Gabby Rudenko  7
Affiliations
  • 1. Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, Texas, 77555, USA; Sealy Center for Structural Biology and Molecular Biophysics, University of Texas Medical Branch, Galveston, Texas, 77555, USA.
  • 2. Nash Family Department of Neuroscience and the Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York, 10029, USA.
  • 3. Department of Neuroscience, Baylor College of Medicine, Houston, Texas, 77030, USA.
  • 4. HTS Screening Core, Center for Translational Cancer Research, Institute of Biosciences and Technology, College of Medicine, Texas A&M University, Houston, Texas, 77030, USA.
  • 5. Chemical Neurobiology Laboratory, Center for Genomic Medicine, Departments of Neurology & Psychiatry, Massachusetts General Hospital & Harvard Medical School, Boston, Massachusetts, 02114, USA.
  • 6. Department of Physiology, Michigan State University, East Lansing, Michigan, 48824, USA.
  • 7. Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, Texas, 77555, USA; Sealy Center for Structural Biology and Molecular Biophysics, University of Texas Medical Branch, Galveston, Texas, 77555, USA. Electronic address: [email protected].
PMID: 41443415 DOI: 10.1016/j.jbc.2025.111080
Abstract

ΔFOSB, 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 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 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 ΔFOSB and Other members of the bZIP transcription factor family.

Keywords
AP-1 transcription factor (AP-1); CUT&RUN; DNA-protein interaction; bZIP domain; druggable sites; gene regulation; small molecule inhibitors of transcription factors; structural biology; transcriptional reprogramming; ΔFOSB.
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