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

Chem Biol Drug Des. 2019 Oct;94(4):1711-1720. doi: 10.1111/cbdd.13564. Epub 2019 Jul 21.

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.

Publication types

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

MeSH terms

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

Substances

  • Indoles
  • NR4A2 protein, human
  • Neoplasm Proteins
  • Nuclear Receptor Subfamily 4, Group A, Member 2
  • Quinolines