Structure-dependent activation of gene expression by bis-indole and quinoline-derived activators of nuclear receptor 4A2

Authors

• Xi Li, Department of Veterinary Physiology and Pharmacology, Texas A&M University, College Station, Texas.
• Ronald B. Tjalkens, Department of Environmental and Radiological Health Sciences, College of Veterinary Medicine and Biomedical Sciences, Colorado State University, Fort Collins, Colorado.Follow
• Rupesh Shrestha, Department of Biochemistry and Biophysics, Texas A&M University, College Station, Texas.
• Stephen Safe, Department of Veterinary Physiology and Pharmacology, Texas A&M University, College Station, Texas.

Document Type

Article

Abstract

Bis-indole derivatives including 1,1-bis(3'-indolyl)-1-(4-chlorophenyl)methane (DIM-C-pPhCl) and substituted quinolines such as chloroquine (CQ) and amodiaquine (AQ) are nuclear receptor 4A2 (NR4A2, Nurr1) ligands, and they exhibit anti-inflammatory activities in mouse and rat models of Parkinson's disease, respectively. However, computational modeling demonstrates that the quinoline derivatives interact with the ligand-binding domain, whereas the bis-indoles preferentially interact with a C-terminal cofactor binding site of NR4A2. In this study, the effects of DIM-C-pPhCl and related analogs were compared with CQ/AQ as inducers of NR4A2-responsive genes including vasoactive intestinal peptide, osteopontin, proopiomelanocortin, and neuropilin 1 in Panc1 and Panc28 pancreatic cancer cells. The results demonstrate that, among the bis-indole analogs, their relative potencies as inducers were structure-gene- and cell context dependent. In contrast, CQ and AQ were significantly less potent than the bis-indole derivatives and, for some of the NR4A2-regulated genes, CQ and AQ were inactive as inducers. These results demonstrate that although bis-indole and quinoline derivatives have been characterized as activators of NR4A2-dependent gene expression, these two classes of compounds exhibit different activities, indicating that they are selective NR4A2 modulators.

Keywords

NR4A2 ligand, bis-indole-derived, quinoline-derived

Medical Subject Headings

Animals; Cell Line, Tumor; Gene Expression Regulation, Neoplastic (drug effects); Humans; Indoles (chemical synthesis, chemistry, pharmacology); Mice; Neoplasm Proteins (metabolism); Nuclear Receptor Subfamily 4, Group A, Member 2 (agonists, metabolism); Pancreatic Neoplasms (metabolism, pathology); Quinolines (chemical synthesis, chemistry, pharmacology); Rats; Structure-Activity Relationship

Publication Date

10-1-2019

Publication Title

Chemical biology & drug design

E-ISSN

1747-0285

Volume

94

Issue

4

First Page

1711

Last Page

1720

PubMed ID

31102570

Digital Object Identifier (DOI)

10.1111/cbdd.13564

Recommended Citation

Li, Xi; Tjalkens, Ronald B.; Shrestha, Rupesh; and Safe, Stephen, "Structure-dependent activation of gene expression by bis-indole and quinoline-derived activators of nuclear receptor 4A2" (2019). Translational Neuroscience. 2569.
https://scholar.barrowneuro.org/neurobiology/2569