{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,1,16]],"date-time":"2026-01-16T02:00:56Z","timestamp":1768528856732,"version":"3.49.0"},"posted":{"date-parts":[[2025,10,23]]},"group-title":"Neuroscience","reference-count":38,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,10,23]],"date-time":"2025-10-23T00:00:00Z","timestamp":1761177600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.biorxiv.org\/about\/FAQ#license"}],"funder":[{"DOI":"10.13039\/100000026","name":"National Institute on Drug Abuse","doi-asserted-by":"crossref","award":["R01DA040621"],"award-info":[{"award-number":["R01DA040621"]}],"id":[{"id":"10.13039\/100000026","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000026","name":"National Institute on Drug Abuse","doi-asserted-by":"crossref","award":["R01DA040621-03S1"],"award-info":[{"award-number":["R01DA040621-03S1"]}],"id":[{"id":"10.13039\/100000026","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000026","name":"National Institute on Drug Abuse","doi-asserted-by":"crossref","award":["R01DA040621-07S1"],"award-info":[{"award-number":["R01DA040621-07S1"]}],"id":[{"id":"10.13039\/100000026","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100004917","name":"Cancer Prevention and Research Institute of Texas","doi-asserted-by":"crossref","award":["RP150578"],"award-info":[{"award-number":["RP150578"]}],"id":[{"id":"10.13039\/100004917","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000065","name":"National Institute of Neurological Disorders and Stroke","doi-asserted-by":"crossref","award":["NS085171"],"award-info":[{"award-number":["NS085171"]}],"id":[{"id":"10.13039\/100000065","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000049","name":"National Institute on Aging","doi-asserted-by":"crossref","award":["F30AG085919"],"award-info":[{"award-number":["F30AG085919"]}],"id":[{"id":"10.13039\/100000049","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2025,10,23]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                <jats:p>\n                  \u0394FOSB, an unusually stable member of the AP1 family of transcription factors, mediates long-term maladaptations that play a key role in the pathogenesis of drug addiction, cognitive decline, dyskinesias, and several other chronic neurological and psychiatric conditions. We have recently identified that 2-phenoxybenzenesulfonic acid-containing compounds disrupt the binding of \u0394FOSB to DNA\n                  <jats:italic>in vitro<\/jats:italic>\n                  in cell-based assays, and one such compound, JPC0661, disrupts \u0394FOSB binding to genomic DNA\n                  <jats:italic>in vivo<\/jats:italic>\n                  in mouse brain with partial efficiency. JPC0661 binds to a groove outside of the DNA-binding cleft of the \u0394FOSB\/JUND bZIP heterodimer in the co-crystal structure. Here, we generated a panel of analogs of JPC0661 with the goal of establishing structure-activity relationships and improving its\n                  <jats:italic>in vivo<\/jats:italic>\n                  efficacy by replacing the amino-pyrazolone cap moiety with various substituents. We show that one such analog, YL0441, disrupts the binding of \u0394FOSB to DNA\n                  <jats:italic>in vitro<\/jats:italic>\n                  and\n                  <jats:italic>in vivo<\/jats:italic>\n                  , and suppresses \u0394FOSB-function in cell-based assays. Importantly, infusion of YL0441 into the hippocampus of APP mice (a mouse model for Alzheimer\u2019s disease) leads to virtually complete loss of \u0394FOSB bound to genomic DNA by CUT&amp;RUN sequencing. Our findings corroborate that DNA binding\/release of AP1 transcription factors can be controlled via small molecules, even by analogs of a compound that binds to a groove outside of the DNA-binding cleft, and that our lead can be optimized via medicinal chemistry to yield a highly efficacious inhibitor of \u0394FOSB function\n                  <jats:italic>in vivo<\/jats:italic>\n                  . These findings define a strategy to design small-molecule inhibitors for other AP1- and AP1-related transcription factors.\n                <\/jats:p>\n                <jats:sec>\n                  <jats:title>IN BRIEF<\/jats:title>\n                  <jats:p>\n                    We demonstrate the creation of a highly effective inhibitor, YL0441, of \u0394FOSB, an AP1 transcription factor, which decreases the number of \u0394FOSB-bound sites to genomic DNA by \u223c94% upon\n                    <jats:italic>in vivo<\/jats:italic>\n                    infusion to the hippocampus of APP mice, a mouse model for Alzheimer\u2019s disease. This work generates a highly novel probe compound to assess the therapeutic value of \u0394FOSB\n                    <jats:italic>in vivo<\/jats:italic>\n                    , a transcription factor with a critical role in mediating long-term changes in gene expression in several neuropsychiatric disorders in addition to Alzheimer\u2019s disease, including drug addiction, seizure-related cognitive decline, and dyskinesias.\n                  <\/jats:p>\n                <\/jats:sec>","DOI":"10.1101\/2025.10.21.683721","type":"posted-content","created":{"date-parts":[[2025,10,23]],"date-time":"2025-10-23T18:25:12Z","timestamp":1761243912000},"source":"Crossref","is-referenced-by-count":0,"title":["Efficient\n                  <i>in vivo<\/i>\n                  pharmacological inhibition of \u0394FOSB, an AP1 transcription factor, in brain"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0304-4247","authenticated-orcid":false,"given":"Sean","family":"McNeme","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1570-783X","authenticated-orcid":false,"given":"Anil","family":"Kumar","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0061-6820","authenticated-orcid":false,"given":"Yun Young","family":"Yim","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2742-6453","authenticated-orcid":false,"given":"Brandon W.","family":"Hughes","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2495-6037","authenticated-orcid":false,"given":"Corey","family":"St. 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