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

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

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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