Nuclear Receptors in Drug Discovery

Nuclear receptors are a class of proteins that play an essential role in the regulation of gene expression. These receptors are activated by small molecules, including hormones, metabolites, and drugs, and function as ligand-dependent transcription factors. The superfamily of nuclear receptors comprises 48 members classified into several subfamilies, such as steroid hormone receptors, thyroid hormone receptors, and retinoic acid receptors [1].

Nuclear receptors play a critical role in several biological processes, controlling the metabolism, development, and homeostasis of living organisms. Thereby, the dysregulation of nuclear receptor function brings about various diseases, including cancer, metabolic disorders, and autoimmune diseases. As a result, nuclear receptors have inevitably emerged as promising targets in drug discovery [1-3].

In recent years, significant progress has been made in the identification and validation of nuclear receptors as drug targets. Several nuclear receptor-based drugs have been approved for clinical use, including the thyroid hormone receptor agonist levothyroxine and the retinoic acid receptor agonist tazarotene. Additionally, several nuclear receptor agonists and antagonists are currently in clinical trials for various indications [3].

Recent advances in nuclear receptor drug discovery have focused on the identification of coregulators, orphan receptors, and major therapeutic areas [1]. Coregulators are proteins that interact with nuclear receptors and modulate their transcriptional activity. Several coregulators have been found, including coactivators and corepressors, which play critical roles in nuclear receptor signaling. Orphan receptors are nuclear receptors whose endogenous ligands are unknown. These receptors are attractive drug targets because they are involved in several diseases, including cancer and metabolic disorders. Several orphan receptors, including RORα and REV-ERB, have been identified as promising drug targets [4].

In addition, several major therapeutic areas have emerged in nuclear receptor drug discovery, including cancer, metabolic disorders, and inflammatory diseases. Nuclear receptors, such as the androgen receptor, estrogen receptor, and progesterone receptor (Fig. 1), have been implicated in the development and progression of various cancers, and several nuclear receptor-based drugs are in clinical development for cancer therapy [3,5]. Similarly, nuclear receptors such as the peroxisome proliferator-activated receptor (PPAR) and the liver X receptor (LXR) have been targeted for the treatment of metabolic disorders, in particular diabetes and dyslipidemia [6-8].

Figure 1. Ligand positions and conformations generated on the basis of docking results for compounds in the Nuclear Receptor Screening Libraries. The localization of ligand molecules is shown in the receptor binding sites (A: compound F3260-0084, estrogen; B: compound F3161-0400, progesterone).

Chemical screening has been instrumental in the identification of nuclear receptor modulators, and high-throughput screening techniques have enabled the screening of large chemical libraries for nuclear receptor ligands. This approach has led to the identification of several nuclear receptor modulators, including agonists and antagonists, with therapeutic potential [9].

With continued research and development, nuclear receptor-based drugs hold a great potential for the treatment of various diseases. In this connection, Life Chemicals has developed two dedicated Nuclear Receptor Screening Libraries, using either docking or ligand-based approach.

Also offered for your expanded nuclear-receptor based studies are the following Libraries:

• Transcription-related Screening Library
• RNA Focused and Targeted Libraries
• DNA and RNA Polymerase Screening Libraries

Additionally, you may be interested in our related products:

• Anticancer Screening Compound Library
• Anti-inflammatory Screening Compound Library
• Protein-Protein Interactions (PPI) Screening Libraries
• Kinase General Screening Libraries
• Ion Channel Screening Libraries
• Hormone-related Focused Library

Please, contact us at marketing@lifechemicals.com for any additional information and price quotations.

Visit our Website for a detailed product description.

Download SD files with compound structures directly from our Downloads section

Custom compound selection based on specific parameters can be performed on request, with competitive pricing and the most convenient terms provided.

References

1. Sladek, F. M. (2003). Nuclear Receptors as Drug Targets: New Developments in Coregulators, Orphan Receptors and Major Therapeutic Areas. Expert Opinion on Therapeutic Targets, 7(5), 679–684. DOI: 10.1517/14728222.7.5.679
2. Moore, J. T., Collins, J. L., & Pearce, K. H. (2006). The nuclear receptor superfamily and drug discovery. ChemMedChem: Chemistry Enabling Drug Discovery, 1(5), 504-523.
3. Zhao, L., Zhou, S., Gustafsson, J.-A. (2019). Nuclear Receptors: Recent Drug Discovery for Cancer Therapies. Endocrine Reviews, 40:5, 1207–1249, DOI: 10.1210/er.2018-00222
4. Kojetin, D., Burris, T. (2014). REV-ERB and ROR nuclear receptors as drug targets. Nat Rev Drug Discov 13, 197–216. DOI: 10.1038/nrd4100
5. 5Vishnoi, K., Viswakarma, N., Rana, A., & Rana, B. (2020). Transcription factors in cancer development and therapy. Cancers, 12(8), 2296.
6. Monsalve, F.A, Pyarasani, R.D, Delgado-Lopez, F., Moore-Carrasco, R. (2013). Peroxisome proliferator-activated receptor targets for the treatment of metabolic diseases. Mediators Inflamm. 2013;2013:549627. DOI: 10.1155/2013/549627
7. Fessler, M. B. (2018). The challenges and promise of targeting the Liver X Receptors for treatment of inflammatory disease. Pharmacol Ther. 181:1-12. DOI: 10.1016/j.pharmthera.2017.07.010
8. Hong, F., Pan, S., Guo, Y., Xu, P., Zhai, Y. (2019). PPARs as nuclear receptors for nutrient and energy metabolism. Molecules. 24(14):2545.
9. Ishigami-Yuasa M, Kagechika H. (2020). Chemical Screening of Nuclear Receptor Modulators. Int J Mol Sci. 21(15):5512. DOI: 10.3390/ijms21155512.