Journal Article

Efficient in vivo pharmacological inhibition of ΔFOSB, an AP1 transcription factor, in brain

Zhou, Jia, Robison, Alfred J, Rudenko, Gabby, Yim, Yun Young, McNeme, Sean, Li, Yi, Takatka, Nadeen, Chin, Jeannie, Bao, Qichao, Rivera, Matthew, Hughes, Brandon W, Chen, Earnest P, Nestler, Eric J, Kumar, Ashwani, Haggarty, Steve J, Fan, Shanghua, St Romain, Corey, Chen, Haiying, Estill, Molly, Kumar, Anil, Machius, Mischa

2025

Overview

ΔFOSB, 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 ΔFOSB to DNA in cell-based assays, and one such compound, JPC0661, disrupts ΔFOSB binding to genomic DNA in mouse brain with partial efficiency. JPC0661 binds to a groove outside of the DNA-binding cleft of the ΔFOSB/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 efficacy by replacing the amino-pyrazolone cap moiety with various substituents. We show that one such analog, YL0441, disrupts the binding of ΔFOSB to DNA and , and suppresses ΔFOSB-function in cell-based assays. Importantly, infusion of YL0441 into the hippocampus of APP mice (a mouse model for Alzheimer's disease) leads to virtually complete loss of ΔFOSB bound to genomic DNA by CUT&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 ΔFOSB function . These findings define a strategy to design small-molecule inhibitors for other AP1- and AP1-related transcription factors. We demonstrate the creation of a highly effective inhibitor, YL0441, of ΔFOSB, an AP1 transcription factor, which decreases the number of ΔFOSB-bound sites to genomic DNA by ∼94% upon infusion to the hippocampus of APP mice, a mouse model for Alzheimer's disease. This work generates a highly novel probe compound to assess the therapeutic value of ΔFOSB , a transcription factor with a critical role in mediating long-term changes in gene expression in several neuropsychiatric disorders in addition to Alzheimer's disease, including drug addiction, seizure-related cognitive decline, and dyskinesias.

• Publisher: Cold Spring Harbor Laboratory
• Subject: Neuroscience