Nuclear Receptor Drug Discovery Assays and Products

The nuclear receptors (NR) are lipophilic signaling molecule-bound transcription factors that control the activation of target genes. The NR superfamily is encoded by 48 genes in the human genome. The NR superfamily comprises receptors for hormones that work by a similar method, including thyroid hormone, vitamin D, retinoids, steroids, and thyroid hormone.

Creative Biolabs offers a wide variety of nuclear receptors-related assays and products:

• Nuclear Receptor Drug Discovery In Vitro Assays

NRs are a subclass of proteins that are found in cells and are capable of detecting a wide range of substances, including thyroid and steroid hormones. These receptors work in tandem with other proteins to regulate the expression of particular genes, which in turn controls the metabolism, homeostasis, and growth of the organism. Because they may directly bind to DNA and affect the expression of neighboring genes, nuclear receptors are transcription factors. Creative Biolabs offers a large selection of nuclear receptor in vitro assays that can be used to evaluate the therapeutic effects of your candidate against the targets.

• Membrane Protein Tools

Creative Biolabs has developed a comprehensive list of membrane protein tools to support the development of antibodies and other therapeutics. We are dedicated to bringing more value to our clients by providing stock products, more technical resources and custom protein production services.

Structure and Function

A conserved N-terminal DNA-binding domain (DBD) and a C-terminal ligand-binding domain make up an NR's common modular structure (LBD). The ligand-inducible transactivation function 2 (AF-2) domain of the LBD determines ligand selectivity in addition to other functions. An aminoterminal ligand-independent activation function 1 (AF-1) domain can also be found in some NRs. Ligand recognition and cofactor interaction are controlled by the LBD. According to a broad theory of NR signaling, the NR frequently associates with an NR co-repressor complex in the absence of a ligand, which inhibits basal transcription activity. When a ligand binds to an NR, conformational changes are brought about that cause the co-repressor complex to be released and a co-activator complex to be recruited. Chromatin remodeling and subsequent transcriptional activation via a particular hormone response element are facilitated by the recruitment of a co-activator complex (HRE).

Fig.1 NRs are ligand-activated transcription factors that regulate target-gene expression. (Chen, 2008)

Cases of Nuclear Receptors

• Androgen receptor (AR)

The NR superfamily member AR has served as a prime target for pharmaceutical development. Testosterone and dihydrotestosterone are two examples of androgens, which are endogenous steroidal AR ligands (DHT). Prostatic cancer and benign prostate hyperplasia (BPH) are two conditions that have been treated using a variety of synthetic AR ligands, including nonsteroidal ligands. These SARMs focus only on one androgen-mediated function, with no other side effects. The endeavor in AR-targeted drug development has centered on increasing therapeutic potency and tissue selectivity while lowering unfavorable side effects, much to the efforts in drug development for other NRs. Early efforts to develop AR-targeted drugs concentrated on altering endogenous androgens and producing synthetic steroidal AR ligands, such as methyltestosterone for the treatment of male hypogonadism.

• PXR

Xenobiotic NRs have been linked to the transcriptional regulation of drug-metabolizing enzymes and transporters. The xenobiotic NRs are known as master regulators of Phase I and Phase II enzymes and drug transporters are CAR and PXR. When CAR or PXR bind to xenobiotic response elements (XRE) found in the promoter regions of drug-metabolizing enzymes and transporters like cytochrome P450 3A4 (CYP3A4) and multidrug resistance 1, the regulation is accomplished (MDR1).

Reference

1. Chen T. Nuclear receptor drug discovery. Curr Opin Chem Biol. 2008,12(4):418-26.