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Nuclear Receptors Product Listing | Edition 2 Kudzu Pueraria lobata A source of Daidzein Nuclear Receptor Products by Group: • Steroid Hormone Receptor Group • Thyroid Hormone Receptor-like Group • Retinoid X Receptor-like Group • Steroidogenic Factor-like Group Tocris Product Listing Series Contents This listing contains over 150 products from Tocris, including a wide range of nuclear receptor agonists and antagonists available for each nuclear receptor group. Related products are also listed, alongside a selection of relevant scientific literature available from www.tocris.com. Introduction................................................................................... 3 Thyroid Hormone Receptor-like Group (continued) Pregnane X Receptor (PXR) ................................................. 9 Steroid Hormone Receptor Group ........................................... 5 Retinoic Acid Receptors (RAR)......................................... 10 Androgen Receptor (AR) ...................................................... 5 Rev-Erb Receptors ............................................................... 11 Estrogen Receptors (ER) ...................................................... 5 Thyroid Hormone Receptors (TR) .................................... 11 Estrogen-related Receptors (ERR) ..................................... 7 Vitamin D Receptor (VDR) ................................................. 11 ............................................. Glucocorticoid Receptor (GR) 7 Retinoid X Receptor-like Group ............................................ 12 Mineralocorticoid Receptor (MR) ....................................... 7 Hepatocyte Nuclear Factor-4 (HNF-4) Receptors ....... 12 Retinoid X Receptors (RXR) .............................................. 12 Progesterone Receptor (PR) ................................................ 7 Steroidogenic Factor-like Group........................................... 13 Thyroid Hormone Receptor-like Group .................................. 8 Liver Receptor Homolog-1 (LRH-1) ................................. 13 Constitutive Androstane Receptor (CAR) ......................... 8 Steroidogenic Factor-1 (SF-1) ........................................... 13 Farnesoid X Receptors (FXR) .............................................. 8 Related Products ..................................................................... 14 Liver X Receptors (LXR) ....................................................... 8 Aromatase (CYP19) ............................................................. 14 Peroxisome Proliferator-activated Receptors (PPAR) ...... 8 Aryl Hydrocarbon Receptor (AhR) ................................... 14 2 | NUCLEAR RECEPTORS Introduction Nuclear receptors, also referred to as nuclear hormone receptors, are a subset of ligand-activated transcription factors that can bind to specific sites on DNA and recruit transcription machinery, influencing gene expression. The 48 known nuclear receptors have been broadly classified into six main groups according to their sequence, with an additional, non-DNA binding group of receptors – DAX-like receptors (group 0) – also described (Figure 1). Figure 1 | Classification of Nuclear Receptors Group 1: Group 2: Group 3: Group 4: Group 5: Group 6: Thyroid Hormone Retinoid X Steroid Hormone Nerve Growth Steroidogenic Germ Cell Nuclear Receptor-like Receptor-like Receptors Factor IB-like Factor-like Factor Receptors Constitutive Nerve Growth COUP-TF-like Androgen Liver Receptor Androstane Factor IB Germ Cell Nuclear Receptors Receptor Homolog 1 Receptor Receptor Factor Hepatocyte Farnesoid X Estrogen Neuron-derived Steroidogenic Nuclear Factor-4 Receptors Receptors Orphan Receptor 1 Factor 1 Receptors Liver X Retinoid X Estrogen-related Nuclear Receptors Receptors Receptors Receptor-related 1 Glucocorticoid PPAR Tailless-like Receptors Receptor Pregnane X Testicular Mineralocorticoid Receptor Receptors Receptor RAR-related Progesterone Orphan Receptors Receptor Miscellaneous group Retinoic Acid Group 0: Receptors DAX-like Receptors Rev-Erb Receptors DAX1 Thyroid Hormone Receptor Receptors SHP Vitamin D Receptor Receptor www.tocris.com | 3 Tocris Product Listing Series Introduction – continued All nuclear receptors comprise five major domains: an N-terminal regulatory domain, a DNA-binding domain, a hinge region, a ligand-binding domain and a C-terminal domain (Figure 2). Some of these domains, such as the DNA-binding domain, are highly conserved between nuclear receptors whereas others, for example the N-terminal regulatory domain, are more variable. In addition to the phylogenetic classification of nuclear receptors (as described by the Nuclear Receptor Nomenclature Committee), nuclear receptors can also be separated into distinct types according to their functional characteristics. The principal difference between the types is in the location of the unbound nuclear receptor; prior to ligand binding, some nuclear receptors are located in the cytosol in a complex with heat shock proteins, whereas others exist in the nucleus where they bind to DNA in a complex with transcriptional corepressors. The involvement of nuclear receptors in almost every cellular process, coupled with their innate ability to bind ligands and influence transcription, has led to significant drug discovery programs targeted at these receptors. Indeed, synthetic ligands for nuclear receptors such as estrogen receptors, glucocorticoid receptors and peroxisome proliferator-activated receptors, are currently used in the treatment of cancer, inflammatory disorders and metabolic disorders respectively. Further research into the physiological functions of these receptors may identify additional therapeutic targets within the nuclear receptor family. Figure 2 | Canonical Nuclear Receptor Structure N-terminal Domain DNA-binding Domain Ligand-binding Domain C-terminal Domain Hinge Region A/B C E F D Key Functions Key Functions Key Functions • Highly variable structure • Activation function-1 (AF-1) • DNA binding • Activation function-2 (AF-2) • Function unknown • Ligand-independent • Dimerization • Ligand binding transactivation • Transactivation • Dimerization • Nuclear localization • Coregulator binding For further information on nuclear receptor structure and function, please refer to Gronemeyer et al (2004) Nat Rev Drug Discov 3 950 Tocris has a unique collection of products for nuclear receptors, from established biochemical standards to novel and exclusive licensed compounds. The information listed within is correct at the time of printing. For the latest information, and to request free scientific literature, please visit www.tocris.com. 4 | NUCLEAR RECEPTORS Steroid Hormone Receptor Group Steroid hormones and their receptors are involved in a vast range of biological processes, from development to cholesterol regulation. Certain members of this family, such as estrogen receptors and androgen receptors, are also important targets for cancer research due to their involvement in tumor cell proliferation. Category Cat. No. Product Name Description Unit Size Androgen Receptor (AR) Agonists 3812 Cl-4AS-1 Steroidal androgen receptor agonist 10 mg 50 mg 2822 Testosterone Endogenous androgen receptor agonist 50 mg Antagonists 3389 Bicalutamide Non-steroidal androgen receptor antagonist 10 mg 50 mg 4094 Flutamide Non-steroidal androgen receptor antagonist 50 mg 1759 Nilutamide Androgen receptor antagonist. Orally active 100 mg 3923 PF 998425 Non-steroidal androgen receptor antagonist 10 mg Modulators 3813 TFM-4AS-1 Selective androgen receptor modulator (SARM) 10 mg 50 mg Other 4626 Andrographolide Inhibits NF-κB; blocks AR expression 50 mg 3293 Finasteride Type II 5α-reductase inhibitor; antiandrogen 50 mg 4396 Piperlongumine Induces apoptosis; depletes androgen receptors in prostate 10 mg cancer cells 50 mg Estrogen Receptors (ER) Agonists 1417 Daidzein ER agonist. Also induces cell cycle arrest 50 mg 1494 DPN Highly potent ERβ agonist 10 mg 50 mg 4276 ERB 041 Potent ERβ agonist 10 mg 50 mg 2823 α-Estradiol Endogenous ER agonist 50 mg 2824 β-Estradiol Endogenous ER agonist 100 mg 3523 FERb 033 Potent and selective ERβ agonist 10 mg 50 mg 3819 Liquiritigenin Selective ERβ agonist 10 mg 1426 PPT Subtype-selective ERα agonist 10 mg 50 mg 1990 (R,R)-THC Potent subtype-selective ligand; ERα agonist/ERβ antagonist 10 mg 3366 WAY 200070 Selective ERβ agonist 10 mg 50 mg Key products for Estrogen Receptors CF3 H H OH OH CF3 O O F F Me Me F F N N CFC3F3 HS S OH CF3 O O FO Me F F F NO2 O2 CF3 S O OH OH H H O O F O2 N HO HO N OH H HO HO O O O N H HH H NN N N S S H HO HO HOO O NN NH HO H H O OH OH N N S ERB 041 N HHOO H ERB 041 HO O OH ERB 041 (4276) ICI 182,780 (1047) LiquiritigeninLiquiritigeninLiquiritigenin (3819) ERB 041 ICI 182,780ICI 182,780 (1047) (1047) HO Potent ERβ agonist ER antagonist LiquiritigeninSelective ERβ agonist GSK 4716 ICI 182,780 (1047) GSK 4716 GSK 4716 F F F CF3 CF3 GSK 9027 GSK 9027 O CF3 HO2C N O O GSK 9027 HO2C N O S N O O O CO2H N S NH O S CO H O N N O HO2C N O 2 O O Ph O NH S O O Ph S O CO H OEt N OS N O O N O O 2 N S O NH O S O OEt O O O N N H O Ph H O O O O O NH O H S H N Et OEt Cl O O HN NH N O N N Et O Tesaglitazar Cl H O O HN H O NH Pioglitazone Tesaglitazar N Et Cl O HN O Pioglitazone Tesaglitazar GSK 3787 (3961)www.tocris.com | 5 O O2N Pioglitazone GSK 3787 (3961) F3C O2N F3C GSK 3787 (3961) O2N F3C SR 1664 (4409) GW 6471 (4618) SR 1664 (4409) GW 6471 (4618) SR 1664 (4409) GW 6471 (4618) CO2H N CO2H CO Et 2 N CO2H NO CO2Et N 2 S S HO O CO2H N O N S NO CO2Et
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