Biology subjects

Chen, E. P.

Publications and source records attributed to Chen, E. P..

3 recordsLinked to original sources

bioRxiv2025

Discovery of Small Molecules and a Druggable Groove That Regulate DNA Binding and Release of the AP1 Transcription Factor DeltaFOSB

{Delta}FOSB, 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 {Delta}FOSB, 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 {Delta}FOSB bZIP -helix from binding to the major groove of DNA. In vivo, direct administration of one such compound, JPC0661, into the brain reduces {Delta}FOSB 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 {Delta}FOSB and other members of the bZIP transcription factor family.

neuroscience↗

bioRxiv2025

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

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

neuroscience↗

bioRxiv2020

A Probabilistic and Anisotropic Failure Metric for Ascending Thoracic Aortic Aneurysm Risk Stratification

Experimental studies have shown that aortic wall tensile strengths in circumferential and longitudinal directions are different (i.e., anisotropic), and vary significantly among patients with aortic aneurysm. To assess aneurysm rupture and dissection risk, material failure metric of the aortic wall needs to be accurately defined and determined. Previously such risk assessment methods have largely relied on deterministic or isotropic failure metric. In this study, we develop a novel probabilistic and anisotropic failure metric for risk stratification of ascending thoracic aortic aneurysm (ATAA). To this end, uniaxial tensile tests were performed using aortic tissue samples of 84 ATAA patients, from which a joint probability distribution of the anisotropic wall strengths was obtained. Next, the anisotropic failure probability (FP) based on the Tsai-Hill (TH) failure criterion was derived. The novel FP metric, which incorporates uncertainty in the anisotropic failure properties, can be evaluated after the aortic wall stresses are computed from patient-specific biomechanical analysis. For method validation, "ground-truth" risks of additional 41 ATAA patients were numerically-reconstructed using corresponding CT images and tissue testing data. Performance of different risk stratification methods (e.g., with and without patient-specific hyperelastic properties) was compared using p-value and receiver operating characteristic (ROC) curve. The results show that: (1) the probabilistic FP metric outperforms the deterministic TH metric; and (2) patient-specific hyperelastic properties can help to improve the performance of probabilistic FP metric in ATAA risk stratification.

bioengineering↗