Nuclear Receptors as Drug Targets: A Historical Perspective of Modern Drug Discovery

Ottow, Eckhard; Weinmann, Hilmar

doi:10.1002/9783527623297.ch1

Cited by 19 publications

(20 citation statements)

References 104 publications

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“…NRs are also known to play a role in various pathological processes including cancer, inflammation and metabolic disorders (McKenna & O'Malley 2010) and as such have been targets of intensive drug development for decades (Ottow & Weinmann 2008).…”

Section: The Nuclear Receptor Superfamilymentioning

confidence: 99%

Emerging functional roles of nuclear receptors in breast cancer

Doan

Graham

2017

Journal of Molecular Endocrinology

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Nuclear receptors (NRs) have been targets of intensive drug development for decades due to their roles as key regulators of multiple developmental, physiological and disease processes. In breast cancer, expression of the estrogen and progesterone receptor remains clinically important in predicting prognosis and determining therapeutic strategies. More recently, there is growing evidence supporting the involvement of multiple nuclear receptors other than the estrogen and progesterone receptors, in the regulation of various processes important to the initiation and progression of breast cancer. We review new insights into the mechanisms of action of NRs made possible by recent advances in genomic technologies and focus on the emerging functional roles of NRs in breast cancer biology, including their involvement in circadian regulation, metabolic reprogramming and breast cancer migration and metastasis.

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Section: The Nuclear Receptor Superfamilymentioning

confidence: 99%

Emerging functional roles of nuclear receptors in breast cancer

Doan

Graham

2017

Journal of Molecular Endocrinology

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“…Molecules such as tamoxifen for estrogen receptors (ER) used for breast cancer, thiazolidinediones for peroxisome proliferator-activated receptor-gamma (PPARγ) used for type II diabetes, mifepristone for the progesterone receptor (PR) used for fertility, and dexamethasone for the glucocorticoid receptor (GR) used for inflammatory diseases, are among the prominent examples of prescription drugs that target NRs (Gronemeyer et al 2004). By some estimates, NR ligands constitute 10–20% of the worldwide pharmaceutical market (Ottow and Weinmann 2008). …”

Section: Introductionmentioning

confidence: 99%

Understanding nuclear receptor form and function using structural biology

Rastinejad

Huang

Chandra

et al. 2013

Journal of Molecular Endocrinology

172

153

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Nuclear receptors (NR) are a major transcription factor family whose members selectively bind small molecule lipophilic ligands and transduce those signals into specific changes in gene programs. For over two decades, structural biology efforts were directed exclusively on the individual ligand binding domains (LBDs) or DNA binding domains (DBDs) of NRs. These analyses revealed the basis for both ligand and DNA binding, and also revealed receptor conformations representing both the activated and repressed states. Additionally, crystallographic studies explained how NR LBD surfaces recognize discrete portions of transcriptional coregulators. The many structural snapshots of LBDs have also guided the development of synthetic ligands with therapeutic potential. Yet, the exclusive structural focus on isolated NR domains has made it difficult to conceptualize how all the NR polypeptide segments are coordinated physically and functionally in the context of receptor quaternary architectures. Newly emerged crystal structures of the PPARγ-RXRα heterodimer and HNF-4α homodimer have recently revealed the higher order organizations of these receptor complexes on DNA, as well as the complexity and uniqueness of their domain-domain interfaces. These emerging structural advances promise to better explain how signals in one domain can be allosterically transmitted to distal receptor domains, also providing much better frameworks for guiding future drug discovery efforts.

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“…[12] They mediate transcriptional responses to hormones and other metabolic ligands through co-activators and co-repressors activity. The ligand induced transcription involves recruitment of co-activators complexes whereas orphan nuclear receptor involves recruitment of co-repressor complexes.…”

Section: Introductionmentioning

confidence: 99%

A chemogenomics based approach for deorphanization of testicular receptor 4: An orphan receptor of nuclear receptor superfamily

Deshmukh

Madagi

2013

J Nat Sc Biol Med

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Orphan Receptor of Nuclear Receptor superfamily is the one with no known endogenous ligands. Many of these orphan receptors are associated with different types of diseases and therefore deserve special attention to find the potential ligands they would be associated with. The major task of molecular pharmacology is the deorphanization of the large number of nuclear receptors with unidentified endogenous agonists. The deorphanization provides a promising research for new therapeutics. The Testicular Receptor 4 being negative modulator to other members of the nuclear receptor superfamily, is one of the Orphan members of this family and is associated with prostate cancer, breast cancer, sickle cell anemia and joint diseases. The knowledge that related receptors of the same family often have ligands with similar structural features has helped us to utilize the chemogenomic approach to deorphanize the orphan receptor. Chemogenomics approach involves screening of known ligands of a protein family having analogous domain architecture for identification of new leads for existing protein family members. The deorphanization involved the database homology searching, followed by domain identification, active site prediction, sequence and structure comparative studies. A ligand library set was prepared based on these studies and was used to deorphanize the receptor. The molecular docking study conducted using PyRx revealed that estradiol and tretinion as a potential ligand for Testicular Receptor 4.

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Nuclear Receptors as Drug Targets: A Historical Perspective of Modern Drug Discovery

Cited by 19 publications

References 104 publications

Emerging functional roles of nuclear receptors in breast cancer

Emerging functional roles of nuclear receptors in breast cancer

Understanding nuclear receptor form and function using structural biology

A chemogenomics based approach for deorphanization of testicular receptor 4: An orphan receptor of nuclear receptor superfamily

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