{"doi":"10.1101/2025.10.21.683675","title":"Discovery of Small Molecules and a Druggable Groove That Regulate DNA Binding and Release of the AP1 Transcription Factor ΔFOSB","abstract":"ABSTRACT ΔFOSB, a member of the AP1 family of transcription factors, mediates long-term neuroadaptations underlying drug addiction, seizure-related cognitive decline, dyskinesias, and several other chronic conditions. AP1 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 AP1 consensus sites by approximately 60% as determined by CUT&RUN-sequencing. These findings suggest that DNA binding and release by AP1 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 AP1-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.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2025,"id":556849,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":2,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9537,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1456532,"name":"Y.-I. Yim","orcid":"0000-0002-7533-3569","position":1,"is_corresponding":false},{"id":915521,"name":"Ashwani Kumar","orcid":"0000-0002-6727-1521","position":2,"is_corresponding":false},{"id":524113,"name":"Yi Li","orcid":"0000-0001-6024-9973","position":3,"is_corresponding":false},{"id":481500,"name":"Brandon W. Hughes","orcid":"0000-0002-2742-6453","position":4,"is_corresponding":false},{"id":362051,"name":"Corey P. St. Romain","orcid":"0000-0002-2495-6037","position":5,"is_corresponding":false},{"id":524114,"name":"Galina V. Aglyamova","orcid":"0000-0001-6105-6399","position":6,"is_corresponding":false},{"id":915524,"name":"Jianping Chen","orcid":"0000-0001-5685-8581","position":7,"is_corresponding":false},{"id":915522,"name":"Nghi Nguyen","orcid":"0000-0001-9379-5401","position":8,"is_corresponding":false},{"id":915525,"name":"Shanghua Fan","orcid":"0000-0002-6596-8472","position":9,"is_corresponding":false},{"id":362049,"name":"Gabriel S. 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Robison","orcid":"0000-0002-4150-9570","position":19,"is_corresponding":false},{"id":383918,"name":"Haiying Chen","orcid":"0000-0003-2841-5518","position":20,"is_corresponding":false},{"id":397258,"name":"Reid T. Powell","orcid":"0000-0002-6242-8315","position":21,"is_corresponding":false},{"id":254137,"name":"Stephen J. Haggarty","orcid":"0000-0002-7872-168X","position":22,"is_corresponding":false},{"id":397268,"name":"Clifford Stephan","orcid":"0000-0003-0657-6484","position":23,"is_corresponding":false},{"id":196103,"name":"Eric J. Nestler","orcid":"0000-0002-7905-2000","position":24,"is_corresponding":false},{"id":362056,"name":"Jeannie Chin","orcid":"0000-0001-9902-3744","position":25,"is_corresponding":false},{"id":30205,"name":"Mischa Machius","orcid":"0000-0002-6040-1362","position":26,"is_corresponding":false},{"id":107272,"name":"Jia Zhou","orcid":"0000-0002-2811-1090","position":27,"is_corresponding":false},{"id":916065,"name":"Gabby Rudenko","orcid":null,"position":28,"is_corresponding":false},{"id":1423969,"name":"Sean McNeme","orcid":"0000-0003-0304-4247","position":0,"is_corresponding":true}],"reference_count":58,"raw_metadata":null,"created_at":"2026-07-19T02:55:13.130091Z","pmid":"41279307","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}