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

Xi Li, Ronald B. Tjalkens, Rupesh Shrestha, Stephen Safe

Research output: Contribution to journalReview articlepeer-review

13 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)1711-1720
Number of pages10
JournalChemical Biology and Drug Design
Issue number4
StatePublished - Oct 1 2019


  • NR4A2 ligand
  • bis-indole-derived
  • quinoline-derived

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Pharmacology
  • Drug Discovery
  • Organic Chemistry


Dive into the research topics of 'Structure-dependent activation of gene expression by bis-indole and quinoline-derived activators of nuclear receptor 4A2'. Together they form a unique fingerprint.

Cite this