Orphan nuclear receptor 4A1 (NR4A1) and novel ligands

Abstract

The nuclear receptor (NR) superfamily of transcription factors encodes expression of 48 human genes that are important for maintaining cellular homeostasis and in pathophysiology, and this has been observed for all sub-families including orphan receptors for which endogenous ligands have not yet been identified. The orphan NR4A1 (Nur77 and TR3) and other members of this sub-family (NR4A2 and NR4A3) are immediate early genes induced by diverse stressors, and these receptors play an important role in the immune function and are up-regulated in some inflammatory diseases including solid tumors. Although endogenous ligands for NR4A have not been identified, several different classes of compounds have been characterized as NR4A1 ligands that bind the receptor. These compounds include cytosporone B and structurally related analogs, bis-indole derived (CDIM) compounds, the triterpenoid celastrol and a number of other chemicals including polyunsaturated fatty acids. NR4A1 ligands bind different regions/surfaces of NR4A1 and exhibit selective NR4A1 modulator (SNR4AM) activities that are dependent on ligand structure and cell/tissue context. NR4A1 ligands exhibit pharmacologic activities in studies on cancer, endometriosis metabolic and inflammatory diseases and are promising agents with clinical potential for treating multiple diseases.

NR4A nuclear receptors in T and B lymphocytes: Gatekeepers of immune tolerance*

“…Crystal structures suggest that their ligand‐binding pocket is occluded and adopts an active conformation that mimics other ligand‐bound nuclear receptors 29,30 . However, small molecule agonist and antagonist ligands (that bind in various locations) have been described, suggesting these TFs may nevertheless be druggable 31‐34 . Furthermore, some recent work has re‐opened the possibility that there may also be endogenous ligands for the NR4A family, although this has yet to be validated in a broad range of contexts 35 …”

Nuclear receptors: from molecular mechanisms to therapeutics

“…In this issue, Lith and de Vries summarize the current knowledge on Nur77's role in inflammation and highlight its potential in the therapeutic intervention of atherosclerosis, inflammatory bowel disease, multiple sclerosis, rheumatoid arthritis, and sepsis [53]. In addition, Safe et al describe the therapeutic potential of Nur77, describing how novel, non-classical ligands bind different parts of Nur77, thereby enabling pharmacologic modulation of this orphan receptor [54].…”

NR4A Family Genes: A Review of Comprehensive Prognostic and Gene Expression Profile Analysis in Breast Cancer

“…They have physiological and pathological roles in the human body specifically regulating homeostasis, proliferation, cell migration, apoptosis, metabolism, DNA repair, glucose utilization, and tumorigenesis ( 12 – 14 ). No endogenous ligand has been identified for these nuclear receptors, but they are considered constitutively active ( 11 , 15 ). Although ligands are not identified, some compounds characterized as ligands that bind the receptor ( 8 , 15 ).…”

“…No endogenous ligand has been identified for these nuclear receptors, but they are considered constitutively active ( 11 , 15 ). Although ligands are not identified, some compounds characterized as ligands that bind the receptor ( 8 , 15 ). One compound, Cytosporone B (CnsB), an NR4A agonist, has been shown to have increased pro-inflammatory mediators when compared to a control that did not have CnsB ( 15 , 16 ).…”

“…Although ligands are not identified, some compounds characterized as ligands that bind the receptor ( 8 , 15 ). One compound, Cytosporone B (CnsB), an NR4A agonist, has been shown to have increased pro-inflammatory mediators when compared to a control that did not have CnsB ( 15 , 16 ). NR4A1-3 is commonly considered a molecular switch, and its actions are regulated by a complex network of cellular signaling pathways ( 11 ).…”