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Review
. 2012 Jan 27;19(1):51-9.
doi: 10.1016/j.chembiol.2011.12.011.

Targeting orphan nuclear receptors for treatment of metabolic diseases and autoimmunity

Thomas P Burris  1 , Scott A Busby, Patrick R Griffin
Affiliations
Review

Targeting orphan nuclear receptors for treatment of metabolic diseases and autoimmunity

Thomas P Burris et al. Chem Biol. .

Abstract

The nuclear receptor (NR) superfamily is composed of 48 members in humans and includes receptors for steroid hormones, thyroid hormone, various lipids and oxysterols. This superfamily has been a rich source of drug targets for myriad diseases including inflammation, cancer, and metabolic disorders. Approximately half of the superfamily have well characterized natural ligands whereas the remaining receptors are considered orphan receptors and remain a focus of a number of investigators assessing their ability to be regulated by ligands. Here, we review recent discoveries that yield important insight into the druggability of three orphan nuclear receptors: the retinoic acid receptor-like orphan receptors (RORs), peroxisome proliferator-activated receptor γ (PPARγ), and liver receptor homolog-1 (LRH-1).

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Figures

Figure 1
Figure 1
Structural domain organization of nuclear receptors. Regions (A/B, C, D, E, and F) are indicated above the schematic and domains are indicated below the schematic. AF=Activation function, DBD=DNA binding domain, LBD=Ligand binding domain.
Figure 2
Figure 2
Chemical structure of several ROR ligands including sterol derivatives (cholesterol, cholesterol sulfate, 7α-hydroxycholesterol, ursolic acid, and digoxin as well as its derivatives) and non-steroidal compounds such as T0901317 and SR1001.
Figure 3
Figure 3
A. Chemical structure of various PPARγ agonists, partial agonists, and “non-agonists”. B. The desired profile of a PPARγ modulator is high affinity binding with minimal to no classical agonism and potent blockage of S273 phosphorylation by CDK5. A compound with this profile will result in improved therapeutic index (maximal efficacy with minimal side effects).
Figure 4
Figure 4
Chemical structure of DLPC and DUPC (Dilauroyl phosphatidylcholine and diundecanoyl phosphatidylcholine), two LRH-1 ligands.
See this image and copyright information in PMC

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