Discovery of phenanthridine analogues as novel chemical probes disrupting the binding of DNA to ΔFosB homodimers and ΔFosB/JunD heterodimers

Li, Yang; Liu, Zhiqing; Aglyamova, Galina V.; Chen, Jianping; Chen, Haiying; Bhandari, Mukund; White, Mark A.; Rudenko, Gloria; Zhou, Jia

doi:10.1016/j.bmcl.2020.127300

Cited by 5 publications

(7 citation statements)

References 21 publications

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“…Excitingly, collaborations involving our groups, structural biologists, and medicinal chemists have uncovered compounds targeting ΔFOSB, 115 and multiple classes of compounds targeting ΔFOSB/DNA interactions are rapidly coming to light. 136 We are employing a strategy informed by protein structural data, taking advantage of the findings from our groups and others demonstrating novel ΔFOSB conformations, oligomerization partners (e.g., heterodimers vs homodimers and potential multimers), and post-translational modifications like oxidation or phosphorylation. We are using cell-free, cell-based, and mouse model assays to screen existing compound libraries to find compound scaffolds that can then be further modified by medicinal chemistry to refine and improve specificity, efficacy, and bioavailability in an iterative process.…”

Section: ■ δFosb Structure and Functionmentioning

confidence: 99%

“…Excitingly, collaborations involving our groups, structural biologists, and medicinal chemists have uncovered compounds targeting ΔFOSB, and multiple classes of compounds targeting ΔFOSB/DNA interactions are rapidly coming to light . We are employing a strategy informed by protein structural data, taking advantage of the findings from our groups and others demonstrating novel ΔFOSB conformations, oligomerization partners (e.g., heterodimers vs homodimers and potential multimers), and post-translational modifications like oxidation or phosphorylation.…”

Section: δFosb As a Medicinal Targetmentioning

confidence: 99%

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ΔFOSB: A Potentially Druggable Master Orchestrator of Activity-Dependent Gene Expression

Robison

Nestler

2022

ACS Chem. Neurosci.

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ΔFOSB is a uniquely stable member of the FOS family of immediate early gene AP1 transcription factors. Its accumulation in specific cell types and tissues in response to a range of chronic stimuli is associated with biological phenomena as diverse as memory formation, drug addiction, stress resilience, and immune cell activity. Causal connections between ΔFOSB expression and the physiological and behavioral sequelae of chronic stimuli have been established in rodent and, in some cases, primate models for numerous healthy and pathological states with such preclinical observations often supported by human data demonstrating tissue-specific ΔFOSB expression associated with several specific syndromes. However, the viability of ΔFOSB as a target for therapeutic intervention might be questioned over presumptive concerns of side effects given its expression in such a wide range of cell types and circumstances. Here, we summarize numerous insights from the past three decades of research into ΔFOSB structure, function, mechanisms of induction, and regulation of target genes that support its potential as a druggable target. We pay particular attention to the potential for targeting distinct ΔFOSB isoforms or distinct ΔFOSB-containing multiprotein complexes to achieve cell type or tissue specificity to overcome off-target concerns. We also cover critical gaps in knowledge that currently limit the exploitation of ΔFOSB’s therapeutic possibilities and how they may be addressed. Finally, we summarize both current and potential future strategies for generating small molecules or genetic tools for the manipulation of ΔFOSB in the clinic.

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Section: ■ δFosb Structure and Functionmentioning

confidence: 99%

Section: δFosb As a Medicinal Targetmentioning

confidence: 99%

ΔFOSB: A Potentially Druggable Master Orchestrator of Activity-Dependent Gene Expression

Robison

Nestler

2022

ACS Chem. Neurosci.

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Section: Table 1 Optimization Of Conditions For the Rea...mentioning

confidence: 99%

“…Calcd for C 19 H 13 NO: C,84.11;H,4.83;N,5.16. Found: C,83.98;H,4.94;N,5. IR (KBr): 3370, 3054, 1610(KBr): 3370, 3054, , 1576(KBr): 3370, 3054, , 1525(KBr): 3370, 3054, , 1476(KBr): 3370, 3054, , 1442(KBr): 3370, 3054, , 1412(KBr): 3370, 3054, , 1344(KBr): 3370, 3054, , 1200(KBr): 3370, 3054, , 1165, 610 cm -1 .…”

Section: Paper Synthesismentioning

confidence: 99%

“…4 ΔFosB chemical probe 2 disrupts the binding of DNA to ΔFosB homodimers and ΔFosB/JunD heterodimers, a therapeutic target for the treatment of various disorders of the central nervous system. 5 Phenanthridine derivatives 3 are antibacterial agents that inhibits FtsZ protein, 6 and organometallic complex 4 is a fluorescent material for the OLED 7 emission layer (Figure 1). At present, a wide range of methods for the synthesis of phenanthridine derivatives 5 has been developed, 8 including intra-or intermolecular transition metal catalyzed cross-coupling reactions 9 and photochemical cyclization.…”

mentioning

confidence: 99%

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A Rearrangement of 4-Phenylbenzo[d]oxazoles to Phenanthridin-4-ols

Fisyuk,

Shatsauskas,

Keyn

et al. 2023

Synthesis

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Design of Tracers in Fluorescence Polarization Assay for Extensive Application in Small Molecule Drug Discovery

Hua

Wang

et al. 2023

J. Med. Chem.

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Development of fluorescence polarization (FP) assays, especially in a competitive manner, is a potent and mature tool for measuring the binding affinities of small molecules. This approach is suitable for high-throughput screening (HTS) for initial ligands and is also applicable for further study of the structure−activity relationships (SARs) of candidate compounds for drug discovery. Buffer and tracer, especially rational design of the tracer, play a vital role in an FP assay system. In this perspective, we provided different kinds of approaches for tracer design based on successful cases in recent years. We classified these tracers by different types of ligands in tracers, including peptide, nucleic acid, natural product, and small molecule. To make this technology accessible for more targets, we briefly described the basic theory and workflow, followed by highlighting the design and application of typical FP tracers from a perspective of medicinal chemistry. ■ SIGNIFICANCE• FP assays are potent tools for drug discovery. This perspective highlights the design of tracers, especially molecular selection, linker design, and fluorophore, and classifies tracers by ligand types. • We provide basic principles for developing FP assays and discuss their prospects for high-throughput screening and identification of small molecules as well as their structure−activity relationships. • This perspective elaborates the FP assay design process and its potential applications in small molecule drug discovery.

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Discovery of phenanthridine analogues as novel chemical probes disrupting the binding of DNA to ΔFosB homodimers and ΔFosB/JunD heterodimers

Cited by 5 publications

References 21 publications

ΔFOSB: A Potentially Druggable Master Orchestrator of Activity-Dependent Gene Expression

ΔFOSB: A Potentially Druggable Master Orchestrator of Activity-Dependent Gene Expression

A Rearrangement of 4-Phenylbenzo[d]oxazoles to Phenanthridin-4-ols

Design of Tracers in Fluorescence Polarization Assay for Extensive Application in Small Molecule Drug Discovery

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