Bis-Indole Derivatives as Dual Nuclear Receptor 4A1 (NR4A1) and NR4A2 Ligands

Authors

• Srijana Upadhyay, Department of Veterinary Physiology, Texas A&M University, College Station, TX 77843, USA.
• Amanuel Esayas Hailemariam, Department of Veterinary Physiology, Texas A&M University, College Station, TX 77843, USA.
• Fuada Mariyam, Department of Veterinary Physiology, Texas A&M University, College Station, TX 77843, USA.
• Zahin Hafiz, Department of Chemical Engineering, Texas A&M University, College Station, TX 77843, USA.
• Gregory Martin, Department of Veterinary Physiology, Texas A&M University, College Station, TX 77843, USA.
• Jainish Kothari, Department of Chemical Engineering, Texas A&M University, College Station, TX 77843, USA.
• Evan Farkas, Department of Veterinary Physiology, Texas A&M University, College Station, TX 77843, USA.
• Gargi Sivaram, Department of Biochemistry and Biophysics, Texas A&M University, College Station, TX 77843, USA.
• Logan Bell, Department of Chemistry, University of La Verne, La Verne, CA 91750, USA.
• Ronald Tjalkens, Department of Environmental and Radiological Health Sciences, College of Veterinary Medicine and Biomedical Sciences, Colorado State University, Fort Collins, CO 80526, USA.
• Stephen Safe, Department of Veterinary Physiology, Texas A&M University, College Station, TX 77843, USA.

Document Type

Article

Abstract

Bis-indole derived compounds such as 1,1-bis(3'-indolyl)-1-(3,5-disubstitutedphenyl) methane (DIM-3,5) and the corresponding 4-hydroxyl analogs (DIM8-3,5) are NR4A1 ligands that act as inverse NR4A1 agonists and are potent inhibitors of tumor growth. The high potency of several DIM-3,5 analogs (IC < 1 mg/kg/day), coupled with the >60% similarity of the ligand-binding domains (LBDs) of NR4A1 and NR4A2 and the pro-oncogenic activities of both receptors lead us to hypothesize that these compounds may act as dual NR4A1 and NR4A2 ligands. Using a fluorescence binding assay, it was shown that 22 synthetic DIM8-3,5 and DIM-3,5 analogs bound the LBD of NR4A1 and NR4A2 with most K values in the low µM range. Moreover, the DIM-3,5 and DIM8-3,5 analogs also decreased NR4A1- and NR4A2-dependent transactivation in U87G glioblastoma cells transfected with GAL4-NR4A1 or GAL4-NR4A2 chimeras and a UAS-luciferase reporter gene construct. The DIM-3,5 and DIM8-3,5 analogs were cytotoxic to U87 glioblastoma and RKO colon cancer cells and the DIM-3,5 compounds were more cytotoxic than the DIM8-3,5 compounds. These studies show that both DIM-3,5 and DIM8-3,5 compounds previously identified as NR4A1 ligands bind both NR4A1 and NR4A2 and are dual NR4A1/2 ligands.

Keywords

NR4A1, NR4A2, bis-indole, dual binding

Medical Subject Headings

Humans; Glioblastoma; Ligands; Nuclear Receptor Subfamily 4, Group A, Member 1 (genetics, metabolism); Cell Line, Tumor; Indoles (pharmacology, chemistry); Nuclear Receptor Subfamily 4, Group A, Member 2 (metabolism)

Publication Date

2-27-2024

Publication Title

Biomolecules

E-ISSN

2218-273X

Volume

14

Issue

3

PubMed ID

38540704

Digital Object Identifier (DOI)

10.3390/biom14030284

Recommended Citation

Upadhyay, Srijana; Hailemariam, Amanuel Esayas; Mariyam, Fuada; Hafiz, Zahin; Martin, Gregory; Kothari, Jainish; Farkas, Evan; Sivaram, Gargi; Bell, Logan; Tjalkens, Ronald; and Safe, Stephen, "Bis-Indole Derivatives as Dual Nuclear Receptor 4A1 (NR4A1) and NR4A2 Ligands" (2024). Translational Neuroscience. 2507.
https://scholar.barrowneuro.org/neurobiology/2507