Orphan nuclear receptor transcription factors as drug targets

Abstract

The nuclear receptor (NR) superfamily of ligand-activated receptors plays a key role in maintaining cellular homeostasis and in pathophysiology. NRs can be subdivided into functional activities structural similarity and the existence of endogenous ligands. Most NRs are classified as those that are adopted orphan or orphan receptors which have only possible ligands or no identified endogenous ligands, respectively. In this review, the activities of the complete orphan receptor sub-family of transcription factors have been reviewed with a focus on the effects of possible endogenous (biochemicals), natural product-derived and synthetic ligands. Despite their lack of a bona-fide ligand, the orphan receptors bind structurally diverse compounds that exhibit tissue-specific agonist, antagonist and inverse agonist activities with potential for future development as clinical therapeutics for the treatment of multiple diseases.

Keywords: Orphan nuclear receptors; ligands; transcription.

Figure 1.

Nuclear receptors. a. Structural domains of NRs include the N-terminal domain (NTD; AB), DNA-binding domain (DBD; C), a hinge region (D) and a C-terminal domain (E) which contains the ligand-binding domain (LBD). Some steroid hormone receptors such as ESR1 contain a C-terminal F domain. b. Adopted orphan receptors now have endogenous ligands which have low affinity. c. Endogenous ligands for orphan receptors have not yet been identified.

Figure 2.

NR4A-mediated activation/inactivation of genes can be due to NR4A monomers, homodimers, NR4A:RXR and NR4A/Sp. The receptors bind specific promoter response elements that accommodate the monomers and homodimers and the heterodimeric RXR and NR4A also act as a cofactor to Sp transcription factor. These interactions can be modulated by ligands and their formation is gene promoter and cell context dependent.

Figure 3.

Tamoxifen, a selective ER modulator exhibits tissue-specific receptor agonist/antagonist activities and acts as an ERα agonist in the uterus bone and liver and an antagonist in breast cancer [15,16].

Figure 4.

NR-VO4 contains the NR4A1 ligand celastrol which is bound through its carboxyl group to polyethyleglycol linkers to a VHL E3 ubiquitin ligase [23].

Figure 5.

Endogenous and synthetic molecules that bind ROR include hydroxylated steroidal compounds [43,44] and LY-55716 [45].

Figure 6.

Examples of endogenous LRH-1 ligands include phospholipids phosphatidyl choline and ethanolamine [63].

Figure 7.

Synthetic compounds that bind Rev-Erb, LRH-1 and GCNF. SR9009 and related compounds that bind Rev-Erb [68], RJW100, an LRH-1 agonist [69] and SLA-12 a partial GCNF agonist [70].

Figure 8.

Cytosporone B and related synthetic analogs-NR4A1 ligands that exhibit a wide range of activities [94–101].

Figure 9.

Celastrol and the polyphenolics quercetin, kaempferol and resveratrol natural products that bind NR4A1 and act as inverse agonists to NR4A1-dependent pro-oncogenic activities [102–114].

Figure 10.

Structures of NR4A2 (DIM-4-CI), NR4A1 (DIM-4-OH) and dual NR4A1/2 second generation (DIM8–3,5) and third generation (DIM-3,5) ligands that bind both NR4A1 and NR4A2 [122–132].

Figure 11.

Structures of clinically approved drugs that could be repositioned to target NR4A1 or NR4A2 [141–148] and in multiple diseases including cancer and non-cancer endpoints such as Parkinson’s disease.

Figure 12.

Ligands that bind COUP-TF include several structurally-diverse heterocyclic compounds [176–179].

Figure 13.

Clinically approved drugs, metformin, Binimetinib (MEK162) and Nolotinib that bind TR2 and TR4 and can be used for treatment of metabolic diseases, myeloid leukemia, prostate cancer [182,187,190].

Figure 14.

DSHN: a novel SHP ligand that modulates, cancer development and immune cell function [200].

Figure 15.

Small molecule inhibitors of TLX receptor that exhibit large differences in structure [228,230,231,233].

Figure 16.

Endogenous and synthetic NR2E3 agonists exhibit different structures and exhibit cell context dependent effects [248–251].

Figure 17.

HNF4α ligands that exhibit agonist or inverse agonist activities are structurally diverse and vary from 1–6 rings and different substituent groups [274,275].

Figure 18.

Flavonoid compounds that bind ERR [287,288].

Figure 19.

Synthetic ligands that bind and activate ERRα and SF-1; ligand structures for both receptors are highly variable [290–293].