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

Yi Li; Zhiqing Liu; Galina Aglyamova; Jianping Chen; Haiying Chen; Mukund Bhandari; Mark A White; Gabrielle Rudenko; Jia Zhou

doi:10.1016/j.bmcl.2020.127300

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

Bioorg Med Chem Lett. 2020 Aug 15;30(16):127300. doi: 10.1016/j.bmcl.2020.127300. Epub 2020 Jun 6.

Authors

Yi Li¹, Zhiqing Liu¹, Galina Aglyamova¹, Jianping Chen¹, Haiying Chen¹, Mukund Bhandari¹, Mark A White², Gabrielle Rudenko³, Jia Zhou⁴

Affiliations

¹ Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, TX 77555, United States.
² Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, TX 77555, United States; Sealy Center for Structural Biology and Molecular Biophysics, University of Texas Medical Branch, Galveston, TX 77555, United States.
³ Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, TX 77555, United States; Sealy Center for Structural Biology and Molecular Biophysics, University of Texas Medical Branch, Galveston, TX 77555, United States. Electronic address: garudenk@utmb.edu.
⁴ Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, TX 77555, United States; Sealy Center for Structural Biology and Molecular Biophysics, University of Texas Medical Branch, Galveston, TX 77555, United States. Electronic address: jizhou@utmb.edu.

Abstract

The transcription factor ΔFosB accumulates in response to chronic insults such as drugs of abuse, L-3,4-dihydroxyphenylalanine (l-DOPA) or stress in specific regions of the brain, triggering long lasting neural and behavioral changes that underlie aspects of drug addiction, dyskinesia, and depression. Thus, small molecule chemical probes are urgently needed to investigate biological functions of ΔFosB. Herein we describe the identification of a novel phenanthridine analogue ZL0220 (27) as an active and promising ΔFosB chemical probe with micromolar inhibitory activities against ΔFosB homodimers and ΔFosB/JunD heterodimers.

Keywords: Chemical probes; Fluorescence polarization assay; High-throughput screening; ΔFosB homodimer; ΔFosB/JunD heterodimer.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Binding Sites / drug effects
DNA / chemistry
DNA / drug effects*
Dose-Response Relationship, Drug
Drug Discovery*
Humans
Molecular Docking Simulation
Molecular Structure
Phenanthridines / chemistry
Phenanthridines / pharmacology*
Proto-Oncogene Proteins c-fos / antagonists & inhibitors*
Proto-Oncogene Proteins c-fos / chemistry
Proto-Oncogene Proteins c-jun / antagonists & inhibitors*
Proto-Oncogene Proteins c-jun / chemistry
Structure-Activity Relationship

Substances

JunD protein, human
Phenanthridines
Proto-Oncogene Proteins c-fos
Proto-Oncogene Proteins c-jun
DNA

Grants and funding

R01 DA040621/DA/NIDA NIH HHS/United States