Mifepristone (T3D2907)

IdentificationTaxonomyBiological PropertiesPhysical PropertiesToxicity ProfileSpectraConcentrationsLinksReferencesGene RegulationTargets (23)XML
Targets (23)
Record Information
Version2.0
Creation Date2009-07-21 20:27:46 UTC
Update Date2014-12-24 20:25:53 UTC
Accession NumberT3D2907
Identification
Common NameMifepristone
ClassSmall Molecule
DescriptionA progestational and glucocorticoid hormone antagonist. Its inhibition of progesterone induces bleeding during the luteal phase and in early pregnancy by releasing endogenous prostaglandins from the endometrium or decidua. As a glucocorticoid receptor antagonist, the drug has been used to treat hypercortisolism in patients with nonpituitary cushing syndrome [PubChem]. The two marketed forms of mifepristone are Mifeprex® (mifepristone 200mg) and Korlym™ (mifepristone 300mg). Currently under investigation for use in psychotic depression (phase 3 trials).
Compound Type
  • Abortifacient Agent, Steroidal
  • Amine
  • Contraceptive, Oral, Synthetic
  • Contraceptive, Postcoital, Synthetic
  • Drug
  • Ester
  • Hormone Antagonist
  • Luteolytic Agent
  • Menstruation-Inducing Agent
  • Metabolite
  • Organic Compound
  • Synthetic Compound
Chemical Structure
Thumb
MOLSDFPDBSMILESInChI
Synonyms
Synonym
11-(4-DIMETHYLAMINO-phenyl)-17-hydroxy-13-methyl-17-prop-1-ynyl-1,2,6,7,8,11,12,13,14,15,16,17-dodec ahydro-cyclopenta[a]phenanthren-3-one
Corlux
Korlym
Mefipil
Mifegyne
Mifeprex
Mifepriston
Mifepristona
Mifépristone
Mifepristonum
RU-486
RU486
Chemical FormulaC29H35NO2
Average Molecular Mass429.594 g/mol
Monoisotopic Mass429.267 g/mol
CAS Registry Number84371-65-3
IUPAC Name(10S,11S,14S,15S,17R)-17-[4-(dimethylamino)phenyl]-14-hydroxy-15-methyl-14-(prop-1-yn-1-yl)tetracyclo[8.7.0.0^{2,7}.0^{11,15}]heptadeca-1,6-dien-5-one
Traditional Name(10S,11S,14S,15S,17R)-17-[4-(dimethylamino)phenyl]-14-hydroxy-15-methyl-14-(prop-1-yn-1-yl)tetracyclo[8.7.0.0^{2,7}.0^{11,15}]heptadeca-1,6-dien-5-one
SMILES[H][C@@]12CC[C@@](O)(C#CC)[C@@]1(C)C[C@]([H])(C1=CC=C(C=C1)N(C)C)C1=C3CCC(=O)C=C3CC[C@@]21[H]
InChI IdentifierInChI=1S/C29H35NO2/c1-5-15-29(32)16-14-26-24-12-8-20-17-22(31)11-13-23(20)27(24)25(18-28(26,29)2)19-6-9-21(10-7-19)30(3)4/h6-7,9-10,17,24-26,32H,8,11-14,16,18H2,1-4H3/t24-,25+,26-,28-,29-/m0/s1
InChI KeyInChIKey=VKHAHZOOUSRJNA-GCNJZUOMSA-N
Chemical Taxonomy
Description belongs to the class of organic compounds known as oxosteroids. These are steroid derivatives carrying a C=O group attached to steroid skeleton.
KingdomOrganic compounds
Super ClassLipids and lipid-like molecules
ClassSteroids and steroid derivatives
Sub ClassOxosteroids
Direct ParentOxosteroids
Alternative Parents
Substituents
  • 3-oxosteroid
  • Hydroxysteroid
  • Oxosteroid
  • 17-hydroxysteroid
  • Tertiary aliphatic/aromatic amine
  • Dialkylarylamine
  • Aniline or substituted anilines
  • Cyclohexenone
  • Benzenoid
  • Monocyclic benzene moiety
  • Ynone
  • Cyclic alcohol
  • Tertiary alcohol
  • Cyclic ketone
  • Tertiary amine
  • Ketone
  • Alcohol
  • Organooxygen compound
  • Organonitrogen compound
  • Organopnictogen compound
  • Organic oxygen compound
  • Organic nitrogen compound
  • Carbonyl group
  • Organic oxide
  • Amine
  • Hydrocarbon derivative
  • Aromatic homopolycyclic compound
Molecular FrameworkAromatic homopolycyclic compounds
External Descriptors
Biological Properties
StatusDetected and Not Quantified
OriginExogenous
Cellular Locations
  • Cytoplasm
  • Extracellular
  • Membrane
Biofluid LocationsNot Available
Tissue LocationsNot Available
PathwaysNot Available
Applications
Biological Roles
Chemical RolesNot Available
Physical Properties
StateSolid
AppearanceWhite powder.
Experimental Properties
PropertyValue
Melting Point191-196°C
Boiling PointNot Available
SolubilityPoorly soluble
LogP4.5
Predicted Properties
PropertyValueSource
Water Solubility0.0034 g/LALOGPS
logP5.33ALOGPS
logP5.13ChemAxon
logS-5.1ALOGPS
pKa (Strongest Acidic)12.87ChemAxon
pKa (Strongest Basic)4.89ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count3ChemAxon
Hydrogen Donor Count1ChemAxon
Polar Surface Area40.54 ŲChemAxon
Rotatable Bond Count3ChemAxon
Refractivity132.58 m³·mol⁻¹ChemAxon
Polarizability50.69 ųChemAxon
Number of Rings5ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleYesChemAxon
MDDR-like RuleYesChemAxon
Spectra
Spectra
Spectrum TypeDescriptionSplash KeyDeposition DateView
Predicted GC-MSPredicted GC-MS Spectrum - GC-MS (Non-derivatized) - 70eV, Positivesplash10-0w29-0356900000-2d8af6b9cc4537ce26fd2017-09-01View Spectrum
Predicted GC-MSPredicted GC-MS Spectrum - GC-MS (1 TMS) - 70eV, Positivesplash10-0079-2055900000-6e525ae464b1871d9ebe2017-10-06View Spectrum
Predicted GC-MSPredicted GC-MS Spectrum - GC-MS (Non-derivatized) - 70eV, PositiveNot Available2021-10-12View Spectrum
LC-MS/MSLC-MS/MS Spectrum - , positivesplash10-001i-0332900000-9cbfa7fe6866f246577a2017-09-14View Spectrum
LC-MS/MSLC-MS/MS Spectrum - , positivesplash10-008i-2952100000-aec78774f54c2156c6622017-09-14View Spectrum
LC-MS/MSLC-MS/MS Spectrum - 45V, Positivesplash10-008i-0931000000-ee8279dfb415bc0681f02021-09-20View Spectrum
LC-MS/MSLC-MS/MS Spectrum - 90V, Positivesplash10-05qc-2920000000-0d03d8c581f1c44990422021-09-20View Spectrum
LC-MS/MSLC-MS/MS Spectrum - 60V, Positivesplash10-001i-1930000000-99d6acb871669431c0892021-09-20View Spectrum
LC-MS/MSLC-MS/MS Spectrum - 75V, Positivesplash10-003r-1920000000-303a5d8b0036258c08812021-09-20View Spectrum
LC-MS/MSLC-MS/MS Spectrum - 15V, Positivesplash10-001i-0000900000-7e417e2be2da168b38212021-09-20View Spectrum
LC-MS/MSLC-MS/MS Spectrum - 35V, Positivesplash10-0089-0964600000-5ddcf4202f05b45619f42021-09-20View Spectrum
LC-MS/MSLC-MS/MS Spectrum - 30V, Positivesplash10-0089-0953300000-18649aead8226d5457ec2021-09-20View Spectrum
LC-MS/MSLC-MS/MS Spectrum - 45V, Positivesplash10-008i-0931000000-6b177a9fd1b11cda4eee2021-09-20View Spectrum
LC-MS/MSLC-MS/MS Spectrum - 90V, Positivesplash10-05qc-2920000000-d4339450b67349c7406c2021-09-20View Spectrum
LC-MS/MSLC-MS/MS Spectrum - 30V, Positivesplash10-0089-0953300000-3040f97a5bcf7379d7422021-09-20View Spectrum
LC-MS/MSLC-MS/MS Spectrum - 60V, Positivesplash10-001i-1930000000-75e712433c777112ab392021-09-20View Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, Positivesplash10-001i-0003900000-482e952a320026611e1a2016-08-03View Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, Positivesplash10-0il0-0019500000-0f2300ca0d9d68333f182016-08-03View Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, Positivesplash10-006y-0239000000-3062d0e76d145ad515022016-08-03View Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, Negativesplash10-004i-0000900000-2424eebcdaf0cba228cb2016-08-03View Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, Negativesplash10-004i-1003900000-0d5db361e6c6078d19c62016-08-03View Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, Negativesplash10-0ir9-1209300000-533594d69ffd57a0e51a2016-08-03View Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, Positivesplash10-001i-0000900000-8a86e41d44598870ec342021-10-11View Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, Positivesplash10-001i-0245900000-5a92d3450ccf91b2fea22021-10-11View Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, Positivesplash10-000t-2419000000-7daab3ac34340f53f4f62021-10-11View Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, Negativesplash10-004i-0000900000-a4eb2582acf4a0d738a02021-10-11View Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, Negativesplash10-004i-0001900000-5e48687bc755905f2a3d2021-10-11View Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, Negativesplash10-0gbc-0179400000-0a9aad20761af0cfe7fa2021-10-11View Spectrum
1D NMR1H NMR Spectrum (1D, 400 MHz, CDCl3, experimental)Not Available2014-09-20View Spectrum
1D NMR13C NMR Spectrum (1D, 50.18 MHz, CDCl3, experimental)Not Available2014-09-23View Spectrum
Toxicity Profile
Route of ExposureOral. The absolute bioavailability of a 20 mg oral dose is 69%
Mechanism of ToxicityMifepristone is a cholinesterase or acetylcholinesterase (AChE) inhibitor. A cholinesterase inhibitor (or 'anticholinesterase') suppresses the action of acetylcholinesterase. Because of its essential function, chemicals that interfere with the action of acetylcholinesterase are potent neurotoxins, causing excessive salivation and eye-watering in low doses, followed by muscle spasms and ultimately death. Nerve gases and many substances used in insecticides have been shown to act by binding a serine in the active site of acetylcholine esterase, inhibiting the enzyme completely. Acetylcholine esterase breaks down the neurotransmitter acetylcholine, which is released at nerve and muscle junctions, in order to allow the muscle or organ to relax. The result of acetylcholine esterase inhibition is that acetylcholine builds up and continues to act so that any nerve impulses are continually transmitted and muscle contractions do not stop. Among the most common acetylcholinesterase inhibitors are phosphorus-based compounds, which are designed to bind to the active site of the enzyme. The structural requirements are a phosphorus atom bearing two lipophilic groups, a leaving group (such as a halide or thiocyanate), and a terminal oxygen.
MetabolismHepatic. Hepatic, by Cytochrome P450 3A4 isoenzyme to the N-monodemethylated metabolite (RU 42 633); RU 42 698, which results from the loss of two methyl groups from position 11 beta; and RU 42 698, which results from terminal hydroxylation of the 17–propynyl chain. Route of Elimination: Fecal: 83%; Renal: 9%. Half Life: 18 hours
Toxicity ValuesNot Available
Lethal DoseNot Available
Carcinogenicity (IARC Classification)No indication of carcinogenicity to humans (not listed by IARC).
Uses/SourcesFor the medical termination of intrauterine pregnancy through 49 days' pregnancy. Also indicated to control hyperglycemia secondary to hypercortisolism in adult patients with endogenous Cushing's syndrome who have type 2 diabetes mellitus or glucose intolerance and are not candidates for surgery or have had unsuccessful surgery.
Minimum Risk LevelNot Available
Health EffectsAcute exposure to cholinesterase inhibitors can cause a cholinergic crisis characterized by severe nausea/vomiting, salivation, sweating, bradycardia, hypotension, collapse, and convulsions. Increasing muscle weakness is a possibility and may result in death if respiratory muscles are involved. Accumulation of ACh at motor nerves causes overstimulation of nicotinic expression at the neuromuscular junction. When this occurs symptoms such as muscle weakness, fatigue, muscle cramps, fasciculation, and paralysis can be seen. When there is an accumulation of ACh at autonomic ganglia this causes overstimulation of nicotinic expression in the sympathetic system. Symptoms associated with this are hypertension, and hypoglycemia. Overstimulation of nicotinic acetylcholine receptors in the central nervous system, due to accumulation of ACh, results in anxiety, headache, convulsions, ataxia, depression of respiration and circulation, tremor, general weakness, and potentially coma. When there is expression of muscarinic overstimulation due to excess acetylcholine at muscarinic acetylcholine receptors symptoms of visual disturbances, tightness in chest, wheezing due to bronchoconstriction, increased bronchial secretions, increased salivation, lacrimation, sweating, peristalsis, and urination can occur. Certain reproductive effects in fertility, growth, and development for males and females have been linked specifically to organophosphate pesticide exposure. Most of the research on reproductive effects has been conducted on farmers working with pesticides and insecticdes in rural areas. In females menstrual cycle disturbances, longer pregnancies, spontaneous abortions, stillbirths, and some developmental effects in offspring have been linked to organophosphate pesticide exposure. Prenatal exposure has been linked to impaired fetal growth and development. Neurotoxic effects have also been linked to poisoning with OP pesticides causing four neurotoxic effects in humans: cholinergic syndrome, intermediate syndrome, organophosphate-induced delayed polyneuropathy (OPIDP), and chronic organophosphate-induced neuropsychiatric disorder (COPIND). These syndromes result after acute and chronic exposure to OP pesticides.
SymptomsNearly all of the women who receive mifepristone will report adverse reactions, and many can be expected to report more than one such reaction. About 90% of patients report adverse reactions following administration of misoprostol on day three of the treatment procedure. Side effects include more heavy bleeding than a heavy manstrual period, abdominal pain, uterine cramping, nausea, vomiting, and diarrhea.
TreatmentIf the compound has been ingested, rapid gastric lavage should be performed using 5% sodium bicarbonate. For skin contact, the skin should be washed with soap and water. If the compound has entered the eyes, they should be washed with large quantities of isotonic saline or water. In serious cases, atropine and/or pralidoxime should be administered. Anti-cholinergic drugs work to counteract the effects of excess acetylcholine and reactivate AChE. Atropine can be used as an antidote in conjunction with pralidoxime or other pyridinium oximes (such as trimedoxime or obidoxime), though the use of '-oximes' has been found to be of no benefit, or possibly harmful, in at least two meta-analyses. Atropine is a muscarinic antagonist, and thus blocks the action of acetylcholine peripherally.
Normal Concentrations
Not Available
Abnormal Concentrations
Not Available
DrugBank IDDB00834
HMDB IDHMDB14972
PubChem Compound ID55245
ChEMBL IDCHEMBL1276308
ChemSpider ID49889
KEGG IDC07652
UniProt IDNot Available
OMIM ID
ChEBI ID50692
BioCyc IDNot Available
CTD IDNot Available
Stitch IDMifepristone
PDB ID486
ACToR IDNot Available
Wikipedia LinkMifepristone
References
Synthesis Reference

Narendra Joshi, Anil Khile, Nitin Pradhan, “Novel polymorph form M of mifepristone and process for its preparation.” U.S. Patent US20070105828, issued May 10, 2007.

MSDSLink
General References
  1. Fiala C, Gemzel-Danielsson K: Review of medical abortion using mifepristone in combination with a prostaglandin analogue. Contraception. 2006 Jul;74(1):66-86. Epub 2006 May 19. [16781264 ]
  2. Heikinheimo O, Kekkonen R, Lahteenmaki P: The pharmacokinetics of mifepristone in humans reveal insights into differential mechanisms of antiprogestin action. Contraception. 2003 Dec;68(6):421-6. [14698071 ]
  3. Chabbert-Buffet N, Meduri G, Bouchard P, Spitz IM: Selective progesterone receptor modulators and progesterone antagonists: mechanisms of action and clinical applications. Hum Reprod Update. 2005 May-Jun;11(3):293-307. Epub 2005 Mar 24. [15790602 ]
  4. Spitz IM, Bardin CW, Benton L, Robbins A: Early pregnancy termination with mifepristone and misoprostol in the United States. N Engl J Med. 1998 Apr 30;338(18):1241-7. [9562577 ]
  5. Piaggio G, von Hertzen H, Heng Z, Bilian X, Cheng L: Meta-analyses of randomized trials comparing different doses of mifepristone in emergency contraception. Contraception. 2003 Dec;68(6):447-52. [14698075 ]
  6. Drugs.com [Link]
  7. Mifepristone - Compound Summary. [Link]
Gene Regulation
Up-Regulated Genes
GeneGene SymbolGene IDInteractionChromosomeDetails
Down-Regulated Genes
GeneGene SymbolGene IDInteractionChromosomeDetails

Targets

Target Details
1. Glucocorticoid receptor
General Function:
Zinc ion binding
Specific Function:
Receptor for glucocorticoids (GC). Has a dual mode of action: as a transcription factor that binds to glucocorticoid response elements (GRE), both for nuclear and mitochondrial DNA, and as a modulator of other transcription factors. Affects inflammatory responses, cellular proliferation and differentiation in target tissues. Could act as a coactivator for STAT5-dependent transcription upon growth hormone (GH) stimulation and could reveal an essential role of hepatic GR in the control of body growth. Involved in chromatin remodeling. May play a negative role in adipogenesis through the regulation of lipolytic and antilipogenic genes expression.
Gene Name:
NR3C1
Uniprot ID:
P04150
Molecular Weight:
85658.57 Da
Binding/Activity Constants
TypeValueAssay TypeAssay Source
Inhibitory0.0001 uMNot AvailableBindingDB 18627
Inhibitory0.00024 uMNot AvailableBindingDB 18627
Inhibitory0.0004 uMNot AvailableBindingDB 18627
Inhibitory0.00044 uMNot AvailableBindingDB 18627
Inhibitory0.00068 uMNot AvailableBindingDB 18627
Inhibitory0.00082 uMNot AvailableBindingDB 18627
Inhibitory0.00084 uMNot AvailableBindingDB 18627
Inhibitory0.001 uMNot AvailableBindingDB 18627
Inhibitory0.0011 uMNot AvailableBindingDB 18627
Inhibitory0.0012 uMNot AvailableBindingDB 18627
Inhibitory0.005 uMNot AvailableBindingDB 18627
Inhibitory0.12 uMNot AvailableBindingDB 18627
Inhibitory0.169 uMNot AvailableBindingDB 18627
IC500.000008 uMNot AvailableBindingDB 18627
IC500.0006 uMNot AvailableBindingDB 18627
IC500.0008 uMNot AvailableBindingDB 18627
IC500.00095 uMNot AvailableBindingDB 18627
IC500.001 uMNot AvailableBindingDB 18627
IC500.0011 uMNot AvailableBindingDB 18627
IC500.0016 uMNot AvailableBindingDB 18627
IC500.0032 uMNot AvailableBindingDB 18627
IC500.00468 uMNot AvailableBindingDB 18627
IC500.0048 uMNot AvailableBindingDB 18627
IC500.005 uMNot AvailableBindingDB 18627
IC500.00575 uMNot AvailableBindingDB 18627
IC500.006 uMNot AvailableBindingDB 18627
IC500.00631 uMNot AvailableBindingDB 18627
IC500.0069 uMNot AvailableBindingDB 18627
IC500.011 uMNot AvailableBindingDB 18627
AC500.00 uMTox21_GR_BLA_Antagonist_ratioTox21/NCGC
References
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  21. Jain N, Allan G, Linton O, Tannenbaum P, Chen X, Xu J, Zhu P, Gunnet J, Demarest K, Lundeen S, Murray W, Sui Z: Synthesis and SAR study of novel pseudo-steroids as potent and selective progesterone receptor antagonists. Bioorg Med Chem Lett. 2009 Jul 15;19(14):3977-80. doi: 10.1016/j.bmcl.2009.01.095. Epub 2009 Jan 31. [19217285 ]
  22. Roll DM, Barbieri LR, Bigelis R, McDonald LA, Arias DA, Chang LP, Singh MP, Luckman SW, Berrodin TJ, Yudt MR: The lecanindoles, nonsteroidal progestins from the terrestrial fungus Verticillium lecanii 6144. J Nat Prod. 2009 Nov;72(11):1944-8. doi: 10.1021/np9004882. [19863083 ]
  23. Barker M, Clackers M, Copley R, Demaine DA, Humphreys D, Inglis GG, Johnston MJ, Jones HT, Haase MV, House D, Loiseau R, Nisbet L, Pacquet F, Skone PA, Shanahan SE, Tape D, Vinader VM, Washington M, Uings I, Upton R, McLay IM, Macdonald SJ: Dissociated nonsteroidal glucocorticoid receptor modulators; discovery of the agonist trigger in a tetrahydronaphthalene-benzoxazine series. J Med Chem. 2006 Jul 13;49(14):4216-31. [16821781 ]
  24. Biggadike K, Boudjelal M, Clackers M, Coe DM, Demaine DA, Hardy GW, Humphreys D, Inglis GG, Johnston MJ, Jones HT, House D, Loiseau R, Needham D, Skone PA, Uings I, Veitch G, Weingarten GG, McLay IM, Macdonald SJ: Nonsteroidal glucocorticoid agonists: tetrahydronaphthalenes with alternative steroidal A-ring mimetics possessing dissociated (transrepression/transactivation) efficacy selectivity. J Med Chem. 2007 Dec 27;50(26):6519-34. Epub 2007 Nov 27. [18038970 ]
  25. Tu N, Link JT, Sorensen BK, Emery M, Grynfarb M, Goos-Nilsson A, Nguyen B: Bile acid conjugates of a nonsteroidal glucocorticoid receptor modulator. Bioorg Med Chem Lett. 2004 Aug 16;14(16):4179-83. [15261266 ]
  26. Jin C, Manikumar G, Kepler JA, Cook CE, Allan GF, Kiddoe M, Bhattacharjee S, Linton O, Lundeen SG, Sui Z: Synthesis and identification of novel 11beta-aryl-4',5'-dihydrospiro[estra-4,9-diene-17beta,4'-oxazole] analogs with dissociated antiprogesterone activities. Bioorg Med Chem Lett. 2007 Nov 1;17(21):5754-7. Epub 2007 Aug 29. [17855092 ]
  27. Yates CM, Brown PJ, Stewart EL, Patten C, Austin RJ, Holt JA, Maglich JM, Angell DC, Sasse RZ, Taylor SJ, Uings IJ, Trump RP: Structure guided design of 5-arylindazole glucocorticoid receptor agonists and antagonists. J Med Chem. 2010 Jun 10;53(11):4531-44. doi: 10.1021/jm100447c. [20469868 ]
  28. Clackers M, Coe DM, Demaine DA, Hardy GW, Humphreys D, Inglis GG, Johnston MJ, Jones HT, House D, Loiseau R, Minick DJ, Skone PA, Uings I, McLay IM, Macdonald SJ: Non-steroidal glucocorticoid agonists: the discovery of aryl pyrazoles as A-ring mimetics. Bioorg Med Chem Lett. 2007 Sep 1;17(17):4737-45. Epub 2007 Jun 26. [17616395 ]
  29. von Geldern TW, Tu N, Kym PR, Link JT, Jae HS, Lai C, Apelqvist T, Rhonnstad P, Hagberg L, Koehler K, Grynfarb M, Goos-Nilsson A, Sandberg J, Osterlund M, Barkhem T, Hoglund M, Wang J, Fung S, Wilcox D, Nguyen P, Jakob C, Hutchins C, Farnegardh M, Kauppi B, Ohman L, Jacobson PB: Liver-selective glucocorticoid antagonists: a novel treatment for type 2 diabetes. J Med Chem. 2004 Aug 12;47(17):4213-30. [15293993 ]
  30. Morgan BP, Swick AG, Hargrove DM, LaFlamme JA, Moynihan MS, Carroll RS, Martin KA, Lee E, Decosta D, Bordner J: Discovery of potent, nonsteroidal, and highly selective glucocorticoid receptor antagonists. J Med Chem. 2002 Jun 6;45(12):2417-24. [12036351 ]
  31. Onnis V, Kinsella GK, Carta G, Jagoe WN, Price T, Williams DC, Fayne D, Lloyd DG: Virtual screening for the identification of novel nonsteroidal glucocorticoid modulators. J Med Chem. 2010 Apr 22;53(8):3065-74. doi: 10.1021/jm901452y. [20334371 ]
  32. Clark RD, Ray NC, Blaney P, Crackett PH, Hurley C, Williams K, Dyke HJ, Clark DE, Lockey PM, Devos R, Wong M, White A, Belanoff JK: 2-Benzenesulfonyl-8a-benzyl-hexahydro-2H-isoquinolin-6-ones as selective glucocorticoid receptor antagonists. Bioorg Med Chem Lett. 2007 Oct 15;17(20):5704-8. Epub 2007 Aug 19. [17822897 ]
  33. Clark RD, Ray NC, Williams K, Blaney P, Ward S, Crackett PH, Hurley C, Dyke HJ, Clark DE, Lockey P, Devos R, Wong M, Porres SS, Bright CP, Jenkins RE, Belanoff J: 1H-Pyrazolo[3,4-g]hexahydro-isoquinolines as selective glucocorticoid receptor antagonists with high functional activity. Bioorg Med Chem Lett. 2008 Feb 15;18(4):1312-7. doi: 10.1016/j.bmcl.2008.01.027. Epub 2008 Jan 11. [18226897 ]
  34. Jiang W, Fiordeliso JJ, Allan G, Linton O, Tannenbaum P, Xu J, Zhu P, Gunnet J, Demarest K, Lundeen S, Sui Z: Discovery of novel phosphorus-containing steroids as selective glucocorticoid receptor antagonist. Bioorg Med Chem Lett. 2007 Mar 1;17(5):1471-4. Epub 2006 Oct 5. [17258455 ]
  35. Backes BJ, Hamilton GL, Nguyen P, Wilcox D, Fung S, Wang J, Grynfarb M, Goos-Nilsson A, Jacobson PB, von Geldern TW: Parallel strategies for the preparation and selection of liver-targeted glucocorticoid receptor antagonists. Bioorg Med Chem Lett. 2007 Jan 1;17(1):40-4. Epub 2006 Oct 5. [17070047 ]
  36. Kratschmar DV, Calabrese D, Walsh J, Lister A, Birk J, Appenzeller-Herzog C, Moulin P, Goldring CE, Odermatt A: Suppression of the Nrf2-dependent antioxidant response by glucocorticoids and 11beta-HSD1-mediated glucocorticoid activation in hepatic cells. PLoS One. 2012;7(5):e36774. doi: 10.1371/journal.pone.0036774. Epub 2012 May 11. [22606287 ]
  37. Sipes NS, Martin MT, Kothiya P, Reif DM, Judson RS, Richard AM, Houck KA, Dix DJ, Kavlock RJ, Knudsen TB: Profiling 976 ToxCast chemicals across 331 enzymatic and receptor signaling assays. Chem Res Toxicol. 2013 Jun 17;26(6):878-95. doi: 10.1021/tx400021f. Epub 2013 May 16. [23611293 ]
Target Details
2. Androgen receptor
General Function:
Zinc ion binding
Specific Function:
Steroid hormone receptors are ligand-activated transcription factors that regulate eukaryotic gene expression and affect cellular proliferation and differentiation in target tissues. Transcription factor activity is modulated by bound coactivator and corepressor proteins. Transcription activation is down-regulated by NR0B2. Activated, but not phosphorylated, by HIPK3 and ZIPK/DAPK3.
Gene Name:
AR
Uniprot ID:
P10275
Molecular Weight:
98987.9 Da
Binding/Activity Constants
TypeValueAssay TypeAssay Source
Inhibitory0.00065 uMNot AvailableBindingDB 18627
Inhibitory0.0046 uMNot AvailableBindingDB 18627
Inhibitory0.0084 uMNot AvailableBindingDB 18627
Inhibitory0.0106 uMNot AvailableBindingDB 18627
Inhibitory0.022 uMNot AvailableBindingDB 18627
IC500.001 uMNot AvailableBindingDB 18627
IC500.0022 uMNot AvailableBindingDB 18627
IC500.005 uMNot AvailableBindingDB 18627
IC500.0069 uMNot AvailableBindingDB 18627
IC500.0078 uMNot AvailableBindingDB 18627
IC500.0083 uMNot AvailableBindingDB 18627
IC500.01 uMNot AvailableBindingDB 18627
IC500.0631 uMNot AvailableBindingDB 18627
IC500.089 uMNot AvailableBindingDB 18627
AC500.03 uMNVS_NR_hARNovascreen
AC500.18 uMOT_AR_ARSRC1_0480Odyssey Thera
AC500.52 uMOT_AR_ARSRC1_0960Odyssey Thera
AC500.23 uMTox21_AR_BLA_Antagonist_ratioTox21/NCGC
AC500.00 uMTox21_AR_LUC_MDAKB2_AgonistTox21/NCGC
AC502.23 uMTox21_AR_LUC_MDAKB2_AntagonistTox21/NCGC
References
  1. Du Y, Li Q, Xiong B, Hui X, Wang X, Feng Y, Meng T, Hu D, Zhang D, Wang M, Shen J: Aromatic beta-amino-ketone derivatives as novel selective non-steroidal progesterone receptor antagonists. Bioorg Med Chem. 2010 Jun 15;18(12):4255-68. doi: 10.1016/j.bmc.2010.04.092. Epub 2010 May 24. [20510622 ]
  2. Muddana SS, Price AM, MacBride MM, Peterson BR: 11beta-alkyl-Delta9-19-nortestosterone derivatives: high-affinity ligands and potent partial agonists of the androgen receptor. J Med Chem. 2004 Oct 7;47(21):4985-8. [15456242 ]
  3. Hamann LG, Farmer LJ, Johnson MG, Bender SL, Mais DE, Wang MW, Crombie D, Goldman ME, Jones TK: Synthesis and biological activity of novel nonsteroidal progesterone receptor antagonists based on cyclocymopol monomethyl ether. J Med Chem. 1996 Apr 26;39(9):1778-89. [8627601 ]
  4. Hamann LG, Higuchi RI, Zhi L, Edwards JP, Wang XN, Marschke KB, Kong JW, Farmer LJ, Jones TK: Synthesis and biological activity of a novel series of nonsteroidal, peripherally selective androgen receptor antagonists derived from 1,2-dihydropyridono[5,6-g]quinolines. J Med Chem. 1998 Feb 12;41(4):623-39. [9484511 ]
  5. Zhang P, Terefenko EA, Fensome A, Wrobel J, Winneker R, Lundeen S, Marschke KB, Zhang Z: 6-Aryl-1,4-dihydro-benzo[d][1,3]oxazin- 2-ones: a novel class of potent, selective, and orally active nonsteroidal progesterone receptor antagonists. J Med Chem. 2002 Sep 26;45(20):4379-82. [12238914 ]
  6. Fensome A, Adams WR, Adams AL, Berrodin TJ, Cohen J, Huselton C, Illenberger A, Kern JC, Hudak VA, Marella MA, Melenski EG, McComas CC, Mugford CA, Slayden OD, Yudt M, Zhang Z, Zhang P, Zhu Y, Winneker RC, Wrobel JE: Design, synthesis, and SAR of new pyrrole-oxindole progesterone receptor modulators leading to 5-(7-fluoro-3,3-dimethyl-2-oxo-2,3-dihydro-1H-indol-5-yl)-1-methyl-1H-pyrrole-2-c arbonitrile (WAY-255348). J Med Chem. 2008 Mar 27;51(6):1861-73. doi: 10.1021/jm701080t. Epub 2008 Mar 5. [18318463 ]
  7. Zhang P, Kern JC, Terefenko EA, Fensome A, Unwalla R, Zhang Z, Cohen J, Berrodin TJ, Yudt MR, Winneker RC, Wrobel J: 7-aryl 1,5-dihydro-benzo[e][1,4]oxazepin-2-ones and analogs as non-steroidal progesterone receptor antagonists. Bioorg Med Chem. 2008 Jul 1;16(13):6589-600. doi: 10.1016/j.bmc.2008.05.018. Epub 2008 May 10. [18504132 ]
  8. Kern JC, Terefenko EA, Fensome A, Unwalla R, Wrobel J, Cohen J, Zhu Y, Berrodin TJ, Yudt MR, Winneker RC, Zhang Z, Zhang P: 1,5-Dihydro-benzo[e][1,4]oxazepin-2(1H)-ones containing a 7-(5'-cyanopyrrol-2-yl) group as nonsteroidal progesterone receptor modulators. Bioorg Med Chem Lett. 2008 Sep 15;18(18):5015-7. doi: 10.1016/j.bmcl.2008.08.015. Epub 2008 Aug 9. [18722119 ]
  9. Kern JC, Terefenko E, Trybulski E, Berrodin TJ, Cohen J, Winneker RC, Yudt MR, Zhang Z, Zhu Y, Zhang P: 1-Methyl-1H-pyrrole-2-carbonitrile containing tetrahydronaphthalene derivatives as non-steroidal progesterone receptor antagonists. Bioorg Med Chem Lett. 2010 Aug 15;20(16):4816-8. doi: 10.1016/j.bmcl.2010.06.109. Epub 2010 Jun 25. [20638844 ]
  10. Zhi L, Ringgenberg JD, Edwards JP, Tegley CM, West SJ, Pio B, Motamedi M, Jones TK, Marschke KB, Mais DE, Schrader WT: Development of progesterone receptor antagonists from 1,2-dihydrochromeno[3,4-f]quinoline agonist pharmacophore. Bioorg Med Chem Lett. 2003 Jun 16;13(12):2075-8. [12781198 ]
  11. Fuhrmann U, Hess-Stumpp H, Cleve A, Neef G, Schwede W, Hoffmann J, Fritzemeier KH, Chwalisz K: Synthesis and biological activity of a novel, highly potent progesterone receptor antagonist. J Med Chem. 2000 Dec 28;43(26):5010-6. [11150172 ]
  12. Yates CM, Brown PJ, Stewart EL, Patten C, Austin RJ, Holt JA, Maglich JM, Angell DC, Sasse RZ, Taylor SJ, Uings IJ, Trump RP: Structure guided design of 5-arylindazole glucocorticoid receptor agonists and antagonists. J Med Chem. 2010 Jun 10;53(11):4531-44. doi: 10.1021/jm100447c. [20469868 ]
  13. Akritopoulou-Zanze I, Patel JR, Hartandi K, Brenneman J, Winn M, Pratt JK, Grynfarb M, Goos-Nisson A, Von Geldern TW, Kym PR: Synthesis and biological evaluation of novel, selective, nonsteroidal glucocorticoid receptor antagonists. Bioorg Med Chem Lett. 2004 May 3;14(9):2079-82. [15080982 ]
  14. von Geldern TW, Tu N, Kym PR, Link JT, Jae HS, Lai C, Apelqvist T, Rhonnstad P, Hagberg L, Koehler K, Grynfarb M, Goos-Nilsson A, Sandberg J, Osterlund M, Barkhem T, Hoglund M, Wang J, Fung S, Wilcox D, Nguyen P, Jakob C, Hutchins C, Farnegardh M, Kauppi B, Ohman L, Jacobson PB: Liver-selective glucocorticoid antagonists: a novel treatment for type 2 diabetes. J Med Chem. 2004 Aug 12;47(17):4213-30. [15293993 ]
  15. Morgan BP, Swick AG, Hargrove DM, LaFlamme JA, Moynihan MS, Carroll RS, Martin KA, Lee E, Decosta D, Bordner J: Discovery of potent, nonsteroidal, and highly selective glucocorticoid receptor antagonists. J Med Chem. 2002 Jun 6;45(12):2417-24. [12036351 ]
  16. Krishnan AV, Zhao XY, Swami S, Brive L, Peehl DM, Ely KR, Feldman D: A glucocorticoid-responsive mutant androgen receptor exhibits unique ligand specificity: therapeutic implications for androgen-independent prostate cancer. Endocrinology. 2002 May;143(5):1889-900. [11956172 ]
  17. Sipes NS, Martin MT, Kothiya P, Reif DM, Judson RS, Richard AM, Houck KA, Dix DJ, Kavlock RJ, Knudsen TB: Profiling 976 ToxCast chemicals across 331 enzymatic and receptor signaling assays. Chem Res Toxicol. 2013 Jun 17;26(6):878-95. doi: 10.1021/tx400021f. Epub 2013 May 16. [23611293 ]
Target Details
3. Nuclear receptor subfamily 1 group I member 2
General Function:
Zinc ion binding
Specific Function:
Nuclear receptor that binds and is activated by variety of endogenous and xenobiotic compounds. Transcription factor that activates the transcription of multiple genes involved in the metabolism and secretion of potentially harmful xenobiotics, drugs and endogenous compounds. Activated by the antibiotic rifampicin and various plant metabolites, such as hyperforin, guggulipid, colupulone, and isoflavones. Response to specific ligands is species-specific. Activated by naturally occurring steroids, such as pregnenolone and progesterone. Binds to a response element in the promoters of the CYP3A4 and ABCB1/MDR1 genes.
Gene Name:
NR1I2
Uniprot ID:
O75469
Molecular Weight:
49761.245 Da
Binding/Activity Constants
TypeValueAssay TypeAssay Source
AC501.23 uMATG_PXR_TRANSAttagene
AC502.39 uMATG_PXRE_CISAttagene
References
  1. Kretschmer XC, Baldwin WS: CAR and PXR: xenosensors of endocrine disrupters? Chem Biol Interact. 2005 Aug 15;155(3):111-28. [16054614 ]
  2. Sipes NS, Martin MT, Kothiya P, Reif DM, Judson RS, Richard AM, Houck KA, Dix DJ, Kavlock RJ, Knudsen TB: Profiling 976 ToxCast chemicals across 331 enzymatic and receptor signaling assays. Chem Res Toxicol. 2013 Jun 17;26(6):878-95. doi: 10.1021/tx400021f. Epub 2013 May 16. [23611293 ]
Target Details
4. Progesterone receptor
General Function:
Zinc ion binding
Specific Function:
The steroid hormones and their receptors are involved in the regulation of eukaryotic gene expression and affect cellular proliferation and differentiation in target tissues. Progesterone receptor isoform B (PRB) is involved activation of c-SRC/MAPK signaling on hormone stimulation.Isoform A: inactive in stimulating c-Src/MAPK signaling on hormone stimulation.Isoform 4: Increases mitochondrial membrane potential and cellular respiration upon stimulation by progesterone.
Gene Name:
PGR
Uniprot ID:
P06401
Molecular Weight:
98979.96 Da
Binding/Activity Constants
TypeValueAssay TypeAssay Source
Inhibitory0.00058 uMNot AvailableBindingDB 18627
Inhibitory0.00064 uMNot AvailableBindingDB 18627
Inhibitory0.0011 uMNot AvailableBindingDB 18627
Inhibitory0.015 uMNot AvailableBindingDB 18627
IC500.0029 uMNot AvailableBindingDB 18627
IC500.003 uMNot AvailableBindingDB 18627
IC500.0033 uMNot AvailableBindingDB 18627
IC500.00794 uMNot AvailableBindingDB 18627
IC500.01 uMNot AvailableBindingDB 18627
IC500.000021 uMNot AvailableBindingDB 18627
IC500.000025 uMNot AvailableBindingDB 18627
IC500.000028 uMNot AvailableBindingDB 18627
IC500.000045 uMNot AvailableBindingDB 18627
IC500.00005 uMNot AvailableBindingDB 18627
IC500.000054 uMNot AvailableBindingDB 18627
IC500.0001 uMNot AvailableBindingDB 18627
IC500.00013 uMNot AvailableBindingDB 18627
IC500.00018 uMNot AvailableBindingDB 18627
IC500.0002 uMNot AvailableBindingDB 18627
IC500.00025 uMNot AvailableBindingDB 18627
IC500.0003 uMNot AvailableBindingDB 18627
IC500.0006 uMNot AvailableBindingDB 18627
IC500.0014 uMNot AvailableBindingDB 18627
IC500.0026 uMNot AvailableBindingDB 18627
AC501.85 uMNVS_NR_hPRNovascreen
References
  1. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [11752352 ]
  2. Greb RR, Kiesel L, Selbmann AK, Wehrmann M, Hodgen GD, Goodman AL, Wallwiener D: Disparate actions of mifepristone (RU 486) on glands and stroma in the primate endometrium. Hum Reprod. 1999 Jan;14(1):198-206. [10374120 ]
  3. Sun M, Zhu G, Zhou L: [Effect of mifepristone on the expression of progesterone receptor messenger RNA and protein in uterine leiomyomata]. Zhonghua Fu Chan Ke Za Zhi. 1998 Apr;33(4):227-31. [10682471 ]
  4. Hazra BG, Basu S, Pore VS, Joshi PL, Pal D, Chakrabarti P: Synthesis of 11beta-(4-dimethylaminophenyl)-17beta-hydroxy-17alpha- (3-methyl-1-butynyl)-4, 9-estradien-3-one and 11beta-(4-acetophenyl)- 17beta-hydroxy-17alpha-(3-methyl-1-butynyl)-4, 9-estradien-3-one: two new analogs of mifepristone (RU-486). Steroids. 2000 Mar;65(3):157-62. [10699595 ]
  5. Gao Y, Cheng L, Liu Y: [Failure of mifepristone induced interruption of pregnancy: point mutation at genetic codon 722 in human progesterone receptor gene]. Zhonghua Fu Chan Ke Za Zhi. 1998 Sep;33(9):549-52. [10806733 ]
  6. Jiang J, Wu R, Wang Z: [Effects of mifepristone on expression of estrogen receptor and progesterone receptor in cultured human eutopic and ectopic endometria]. Zhonghua Fu Chan Ke Za Zhi. 2001 Apr;36(4):218-21. [11783365 ]
  7. Hodl C, Raunegger K, Strommer R, Ecker GF, Kunert O, Sturm S, Seger C, Haslinger E, Steiner R, Strauss WS, Schramm HW: Syntheses and antigestagenic activity of mifepristone derivatives. J Med Chem. 2009 Mar 12;52(5):1268-74. doi: 10.1021/jm800985z. [19216549 ]
  8. Fuhrmann U, Hess-Stumpp H, Cleve A, Neef G, Schwede W, Hoffmann J, Fritzemeier KH, Chwalisz K: Synthesis and biological activity of a novel, highly potent progesterone receptor antagonist. J Med Chem. 2000 Dec 28;43(26):5010-6. [11150172 ]
  9. Saha P, Hodl C, Strauss WS, Steiner R, Goessler W, Kunert O, Leitner A, Haslinger E, Schramm HW: Synthesis, in vitro progesterone receptors affinity of gadolinium containing mifepristone conjugates and estimation of binding sites in human breast cancer cells. Bioorg Med Chem. 2010 Mar 1;18(5):1891-8. doi: 10.1016/j.bmc.2010.01.048. Epub 2010 Jan 25. [20149664 ]
  10. Jin C, Manikumar G, Kepler JA, Cook CE, Allan GF, Kiddoe M, Bhattacharjee S, Linton O, Lundeen SG, Sui Z: Synthesis and identification of novel 11beta-aryl-4',5'-dihydrospiro[estra-4,9-diene-17beta,4'-oxazole] analogs with dissociated antiprogesterone activities. Bioorg Med Chem Lett. 2007 Nov 1;17(21):5754-7. Epub 2007 Aug 29. [17855092 ]
  11. Fensome A, Bender R, Cohen J, Collins MA, Mackner VA, Miller LL, Ullrich JW, Winneker R, Wrobel J, Zhang P, Zhang Z, Zhu Y: New progesterone receptor antagonists: 3,3-disubstituted-5-aryloxindoles. Bioorg Med Chem Lett. 2002 Dec 2;12(23):3487-90. [12419390 ]
  12. Zhang P, Terefenko EA, Fensome A, Wrobel J, Winneker R, Lundeen S, Marschke KB, Zhang Z: 6-Aryl-1,4-dihydro-benzo[d][1,3]oxazin- 2-ones: a novel class of potent, selective, and orally active nonsteroidal progesterone receptor antagonists. J Med Chem. 2002 Sep 26;45(20):4379-82. [12238914 ]
  13. Hamann LG, Farmer LJ, Johnson MG, Bender SL, Mais DE, Wang MW, Crombie D, Goldman ME, Jones TK: Synthesis and biological activity of novel nonsteroidal progesterone receptor antagonists based on cyclocymopol monomethyl ether. J Med Chem. 1996 Apr 26;39(9):1778-89. [8627601 ]
  14. Hamann LG, Higuchi RI, Zhi L, Edwards JP, Wang XN, Marschke KB, Kong JW, Farmer LJ, Jones TK: Synthesis and biological activity of a novel series of nonsteroidal, peripherally selective androgen receptor antagonists derived from 1,2-dihydropyridono[5,6-g]quinolines. J Med Chem. 1998 Feb 12;41(4):623-39. [9484511 ]
  15. Zhang P, Terefenko EA, Wrobel J, Zhang Z, Zhu Y, Cohen J, Marschke KB, Mais D: Synthesis and progesterone receptor antagonist activities of 6-aryl benzimidazolones and benzothiazolones. Bioorg Med Chem Lett. 2001 Oct 22;11(20):2747-50. [11591515 ]
  16. Zhang P, Terefenko EA, Fensome A, Zhang Z, Zhu Y, Cohen J, Winneker R, Wrobel J, Yardley J: Potent nonsteroidal progesterone receptor agonists: synthesis and SAR study of 6-aryl benzoxazines. Bioorg Med Chem Lett. 2002 Mar 11;12(5):787-90. [11859003 ]
  17. Fensome A, Adams WR, Adams AL, Berrodin TJ, Cohen J, Huselton C, Illenberger A, Kern JC, Hudak VA, Marella MA, Melenski EG, McComas CC, Mugford CA, Slayden OD, Yudt M, Zhang Z, Zhang P, Zhu Y, Winneker RC, Wrobel JE: Design, synthesis, and SAR of new pyrrole-oxindole progesterone receptor modulators leading to 5-(7-fluoro-3,3-dimethyl-2-oxo-2,3-dihydro-1H-indol-5-yl)-1-methyl-1H-pyrrole-2-c arbonitrile (WAY-255348). J Med Chem. 2008 Mar 27;51(6):1861-73. doi: 10.1021/jm701080t. Epub 2008 Mar 5. [18318463 ]
  18. Zhang P, Kern JC, Terefenko EA, Fensome A, Unwalla R, Zhang Z, Cohen J, Berrodin TJ, Yudt MR, Winneker RC, Wrobel J: 7-aryl 1,5-dihydro-benzo[e][1,4]oxazepin-2-ones and analogs as non-steroidal progesterone receptor antagonists. Bioorg Med Chem. 2008 Jul 1;16(13):6589-600. doi: 10.1016/j.bmc.2008.05.018. Epub 2008 May 10. [18504132 ]
  19. Kern JC, Terefenko EA, Fensome A, Unwalla R, Wrobel J, Cohen J, Zhu Y, Berrodin TJ, Yudt MR, Winneker RC, Zhang Z, Zhang P: 1,5-Dihydro-benzo[e][1,4]oxazepin-2(1H)-ones containing a 7-(5'-cyanopyrrol-2-yl) group as nonsteroidal progesterone receptor modulators. Bioorg Med Chem Lett. 2008 Sep 15;18(18):5015-7. doi: 10.1016/j.bmcl.2008.08.015. Epub 2008 Aug 9. [18722119 ]
  20. Kern JC, Terefenko E, Trybulski E, Berrodin TJ, Cohen J, Winneker RC, Yudt MR, Zhang Z, Zhu Y, Zhang P: 1-Methyl-1H-pyrrole-2-carbonitrile containing tetrahydronaphthalene derivatives as non-steroidal progesterone receptor antagonists. Bioorg Med Chem Lett. 2010 Aug 15;20(16):4816-8. doi: 10.1016/j.bmcl.2010.06.109. Epub 2010 Jun 25. [20638844 ]
  21. Wiethe RW, Stewart EL, Drewry DH, Gray DW, Mehbob A, Hoekstra WJ: Array synthesis of progesterone receptor antagonists: 3-aryl-1,2-diazepines. Bioorg Med Chem Lett. 2006 Jul 15;16(14):3777-9. Epub 2006 May 5. [16678409 ]
  22. Pooley CL, Edwards JP, Goldman ME, Wang MW, Marschke KB, Crombie DL, Jones TK: Discovery and preliminary SAR studies of a novel, nonsteroidal progesterone receptor antagonist pharmacophore. J Med Chem. 1998 Aug 27;41(18):3461-6. [9719599 ]
  23. Zhi L, Tegley CM, Pio B, Edwards JP, Jones TK, Marschke KB, Mais DE, Risek B, Schrader WT: Synthesis and biological activity of 5-methylidene 1,2-dihydrochromeno[3,4-f]quinoline derivatives as progesterone receptor modulators. Bioorg Med Chem Lett. 2003 Jun 16;13(12):2071-4. [12781197 ]
  24. Du Y, Li Q, Xiong B, Hui X, Wang X, Feng Y, Meng T, Hu D, Zhang D, Wang M, Shen J: Aromatic beta-amino-ketone derivatives as novel selective non-steroidal progesterone receptor antagonists. Bioorg Med Chem. 2010 Jun 15;18(12):4255-68. doi: 10.1016/j.bmc.2010.04.092. Epub 2010 May 24. [20510622 ]
  25. Kang FA, Allan G, Guan J, Jain N, Linton O, Tannenbaum P, Xu J, Zhu P, Gunnet J, Chen X, Demarest K, Lundeen S, Sui Z: Synthesis and identification of novel oxa-steroids as progesterone receptor antagonists. Bioorg Med Chem Lett. 2007 Feb 15;17(4):907-10. Epub 2006 Dec 1. [17169557 ]
  26. Kang FA, Guan J, Jain N, Allan G, Linton O, Tannenbaum P, Chen X, Xu J, Zhu P, Gunnet J, Demarest K, Lundeen S, Sui Z: Parallel synthesis and SAR study of novel oxa-steroids as potent and selective progesterone receptor antagonists. Bioorg Med Chem Lett. 2007 May 1;17(9):2531-4. Epub 2007 Feb 8. [17317167 ]
  27. Jain N, Allan G, Linton O, Tannenbaum P, Chen X, Xu J, Zhu P, Gunnet J, Demarest K, Lundeen S, Murray W, Sui Z: Synthesis and SAR study of novel pseudo-steroids as potent and selective progesterone receptor antagonists. Bioorg Med Chem Lett. 2009 Jul 15;19(14):3977-80. doi: 10.1016/j.bmcl.2009.01.095. Epub 2009 Jan 31. [19217285 ]
  28. Jiang W, Fiordeliso JJ, Allan G, Linton O, Tannenbaum P, Xu J, Zhu P, Gunnet J, Demarest K, Lundeen S, Sui Z: Discovery of novel phosphorus-containing steroids as selective glucocorticoid receptor antagonist. Bioorg Med Chem Lett. 2007 Mar 1;17(5):1471-4. Epub 2006 Oct 5. [17258455 ]
  29. Link JT, Sorensen BK, Lai C, Wang J, Fung S, Deng D, Emery M, Carroll S, Grynfarb M, Goos-Nilsson A, Von Geldern T: Synthesis, activity, metabolic stability, and pharmacokinetics of glucocorticoid receptor modulator-statin hybrids. Bioorg Med Chem Lett. 2004 Aug 16;14(16):4173-8. [15261265 ]
  30. Akritopoulou-Zanze I, Patel JR, Hartandi K, Brenneman J, Winn M, Pratt JK, Grynfarb M, Goos-Nisson A, Von Geldern TW, Kym PR: Synthesis and biological evaluation of novel, selective, nonsteroidal glucocorticoid receptor antagonists. Bioorg Med Chem Lett. 2004 May 3;14(9):2079-82. [15080982 ]
  31. Zhi L, Ringgenberg JD, Edwards JP, Tegley CM, West SJ, Pio B, Motamedi M, Jones TK, Marschke KB, Mais DE, Schrader WT: Development of progesterone receptor antagonists from 1,2-dihydrochromeno[3,4-f]quinoline agonist pharmacophore. Bioorg Med Chem Lett. 2003 Jun 16;13(12):2075-8. [12781198 ]
  32. Yates CM, Brown PJ, Stewart EL, Patten C, Austin RJ, Holt JA, Maglich JM, Angell DC, Sasse RZ, Taylor SJ, Uings IJ, Trump RP: Structure guided design of 5-arylindazole glucocorticoid receptor agonists and antagonists. J Med Chem. 2010 Jun 10;53(11):4531-44. doi: 10.1021/jm100447c. [20469868 ]
  33. Abid Masood M, Farrant E, Morao I, Bazin M, Perez M, Bunnage ME, Fancy SA, Peakman T: Lead diversification. Application to existing drug molecules: mifepristone 1 and antalarmin 8. Bioorg Med Chem Lett. 2012 Jan 1;22(1):723-8. doi: 10.1016/j.bmcl.2011.10.066. Epub 2011 Oct 25. [22104142 ]
  34. von Geldern TW, Tu N, Kym PR, Link JT, Jae HS, Lai C, Apelqvist T, Rhonnstad P, Hagberg L, Koehler K, Grynfarb M, Goos-Nilsson A, Sandberg J, Osterlund M, Barkhem T, Hoglund M, Wang J, Fung S, Wilcox D, Nguyen P, Jakob C, Hutchins C, Farnegardh M, Kauppi B, Ohman L, Jacobson PB: Liver-selective glucocorticoid antagonists: a novel treatment for type 2 diabetes. J Med Chem. 2004 Aug 12;47(17):4213-30. [15293993 ]
  35. Morgan BP, Swick AG, Hargrove DM, LaFlamme JA, Moynihan MS, Carroll RS, Martin KA, Lee E, Decosta D, Bordner J: Discovery of potent, nonsteroidal, and highly selective glucocorticoid receptor antagonists. J Med Chem. 2002 Jun 6;45(12):2417-24. [12036351 ]
  36. Jones DG, Liang X, Stewart EL, Noe RA, Kallander LS, Madauss KP, Williams SP, Thompson SK, Gray DW, Hoekstra WJ: Discovery of non-steroidal mifepristone mimetics: pyrazoline-based PR antagonists. Bioorg Med Chem Lett. 2005 Jul 1;15(13):3203-6. [15925510 ]
  37. Sipes NS, Martin MT, Kothiya P, Reif DM, Judson RS, Richard AM, Houck KA, Dix DJ, Kavlock RJ, Knudsen TB: Profiling 976 ToxCast chemicals across 331 enzymatic and receptor signaling assays. Chem Res Toxicol. 2013 Jun 17;26(6):878-95. doi: 10.1021/tx400021f. Epub 2013 May 16. [23611293 ]
Target Details
5. Mineralocorticoid receptor
General Function:
Zinc ion binding
Specific Function:
Receptor for both mineralocorticoids (MC) such as aldosterone and glucocorticoids (GC) such as corticosterone or cortisol. Binds to mineralocorticoid response elements (MRE) and transactivates target genes. The effect of MC is to increase ion and water transport and thus raise extracellular fluid volume and blood pressure and lower potassium levels.
Gene Name:
NR3C2
Uniprot ID:
P08235
Molecular Weight:
107066.575 Da
Binding/Activity Constants
TypeValueAssay TypeAssay Source
Inhibitory0.64 uMNot AvailableBindingDB 18627
Inhibitory>10 uMNot AvailableBindingDB 18627
IC500.59 uMNot AvailableBindingDB 18627
IC501.155 uMNot AvailableBindingDB 18627
IC506 uMNot AvailableBindingDB 18627
IC50>1 uMNot AvailableBindingDB 18627
References
  1. Zhang P, Kern JC, Terefenko EA, Fensome A, Unwalla R, Zhang Z, Cohen J, Berrodin TJ, Yudt MR, Winneker RC, Wrobel J: 7-aryl 1,5-dihydro-benzo[e][1,4]oxazepin-2-ones and analogs as non-steroidal progesterone receptor antagonists. Bioorg Med Chem. 2008 Jul 1;16(13):6589-600. doi: 10.1016/j.bmc.2008.05.018. Epub 2008 May 10. [18504132 ]
  2. Kern JC, Terefenko EA, Fensome A, Unwalla R, Wrobel J, Cohen J, Zhu Y, Berrodin TJ, Yudt MR, Winneker RC, Zhang Z, Zhang P: 1,5-Dihydro-benzo[e][1,4]oxazepin-2(1H)-ones containing a 7-(5'-cyanopyrrol-2-yl) group as nonsteroidal progesterone receptor modulators. Bioorg Med Chem Lett. 2008 Sep 15;18(18):5015-7. doi: 10.1016/j.bmcl.2008.08.015. Epub 2008 Aug 9. [18722119 ]
  3. Kern JC, Terefenko E, Trybulski E, Berrodin TJ, Cohen J, Winneker RC, Yudt MR, Zhang Z, Zhu Y, Zhang P: 1-Methyl-1H-pyrrole-2-carbonitrile containing tetrahydronaphthalene derivatives as non-steroidal progesterone receptor antagonists. Bioorg Med Chem Lett. 2010 Aug 15;20(16):4816-8. doi: 10.1016/j.bmcl.2010.06.109. Epub 2010 Jun 25. [20638844 ]
  4. Zhi L, Ringgenberg JD, Edwards JP, Tegley CM, West SJ, Pio B, Motamedi M, Jones TK, Marschke KB, Mais DE, Schrader WT: Development of progesterone receptor antagonists from 1,2-dihydrochromeno[3,4-f]quinoline agonist pharmacophore. Bioorg Med Chem Lett. 2003 Jun 16;13(12):2075-8. [12781198 ]
  5. Akritopoulou-Zanze I, Patel JR, Hartandi K, Brenneman J, Winn M, Pratt JK, Grynfarb M, Goos-Nisson A, Von Geldern TW, Kym PR: Synthesis and biological evaluation of novel, selective, nonsteroidal glucocorticoid receptor antagonists. Bioorg Med Chem Lett. 2004 May 3;14(9):2079-82. [15080982 ]
  6. Hamann LG, Farmer LJ, Johnson MG, Bender SL, Mais DE, Wang MW, Crombie D, Goldman ME, Jones TK: Synthesis and biological activity of novel nonsteroidal progesterone receptor antagonists based on cyclocymopol monomethyl ether. J Med Chem. 1996 Apr 26;39(9):1778-89. [8627601 ]
  7. Zhang P, Terefenko EA, Fensome A, Wrobel J, Winneker R, Lundeen S, Marschke KB, Zhang Z: 6-Aryl-1,4-dihydro-benzo[d][1,3]oxazin- 2-ones: a novel class of potent, selective, and orally active nonsteroidal progesterone receptor antagonists. J Med Chem. 2002 Sep 26;45(20):4379-82. [12238914 ]
  8. Du Y, Li Q, Xiong B, Hui X, Wang X, Feng Y, Meng T, Hu D, Zhang D, Wang M, Shen J: Aromatic beta-amino-ketone derivatives as novel selective non-steroidal progesterone receptor antagonists. Bioorg Med Chem. 2010 Jun 15;18(12):4255-68. doi: 10.1016/j.bmc.2010.04.092. Epub 2010 May 24. [20510622 ]
  9. von Geldern TW, Tu N, Kym PR, Link JT, Jae HS, Lai C, Apelqvist T, Rhonnstad P, Hagberg L, Koehler K, Grynfarb M, Goos-Nilsson A, Sandberg J, Osterlund M, Barkhem T, Hoglund M, Wang J, Fung S, Wilcox D, Nguyen P, Jakob C, Hutchins C, Farnegardh M, Kauppi B, Ohman L, Jacobson PB: Liver-selective glucocorticoid antagonists: a novel treatment for type 2 diabetes. J Med Chem. 2004 Aug 12;47(17):4213-30. [15293993 ]
Target Details
6. Cytochrome P450 3A4
General Function:
Vitamin d3 25-hydroxylase activity
Specific Function:
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It performs a variety of oxidation reactions (e.g. caffeine 8-oxidation, omeprazole sulphoxidation, midazolam 1'-hydroxylation and midazolam 4-hydroxylation) of structurally unrelated compounds, including steroids, fatty acids, and xenobiotics. Acts as a 1,8-cineole 2-exo-monooxygenase. The enzyme also hydroxylates etoposide (PubMed:11159812). Catalyzes 4-beta-hydroxylation of cholesterol. May catalyze 25-hydroxylation of cholesterol in vitro (PubMed:21576599).
Gene Name:
CYP3A4
Uniprot ID:
P08684
Molecular Weight:
57342.67 Da
Binding/Activity Constants
TypeValueAssay TypeAssay Source
Inhibitory4.7 uMNot AvailableBindingDB 18627
References
  1. Fontana E, Dansette PM, Poli SM: Cytochrome p450 enzymes mechanism based inhibitors: common sub-structures and reactivity. Curr Drug Metab. 2005 Oct;6(5):413-54. [16248836 ]
Target Details
7. Thyroid hormone receptor alpha
General Function:
Zinc ion binding
Specific Function:
Isoform Alpha-1: Nuclear hormone receptor that can act as a repressor or activator of transcription. High affinity receptor for thyroid hormones, including triiodothyronine and thyroxine.Isoform Alpha-2: Does not bind thyroid hormone and functions as a weak dominant negative inhibitor of thyroid hormone action.
Gene Name:
THRA
Uniprot ID:
P10827
Molecular Weight:
54815.055 Da
Binding/Activity Constants
TypeValueAssay TypeAssay Source
Inhibitory>1.25 uMNot AvailableBindingDB 18627
References
  1. von Geldern TW, Tu N, Kym PR, Link JT, Jae HS, Lai C, Apelqvist T, Rhonnstad P, Hagberg L, Koehler K, Grynfarb M, Goos-Nilsson A, Sandberg J, Osterlund M, Barkhem T, Hoglund M, Wang J, Fung S, Wilcox D, Nguyen P, Jakob C, Hutchins C, Farnegardh M, Kauppi B, Ohman L, Jacobson PB: Liver-selective glucocorticoid antagonists: a novel treatment for type 2 diabetes. J Med Chem. 2004 Aug 12;47(17):4213-30. [15293993 ]
Target Details
8. Thyroid hormone receptor beta
General Function:
Zinc ion binding
Specific Function:
Nuclear hormone receptor that can act as a repressor or activator of transcription. High affinity receptor for thyroid hormones, including triiodothyronine and thyroxine.
Gene Name:
THRB
Uniprot ID:
P10828
Molecular Weight:
52787.16 Da
Binding/Activity Constants
TypeValueAssay TypeAssay Source
Inhibitory>2.25 uMNot AvailableBindingDB 18627
References
  1. von Geldern TW, Tu N, Kym PR, Link JT, Jae HS, Lai C, Apelqvist T, Rhonnstad P, Hagberg L, Koehler K, Grynfarb M, Goos-Nilsson A, Sandberg J, Osterlund M, Barkhem T, Hoglund M, Wang J, Fung S, Wilcox D, Nguyen P, Jakob C, Hutchins C, Farnegardh M, Kauppi B, Ohman L, Jacobson PB: Liver-selective glucocorticoid antagonists: a novel treatment for type 2 diabetes. J Med Chem. 2004 Aug 12;47(17):4213-30. [15293993 ]
Target Details
9. Estrogen receptor
General Function:
Zinc ion binding
Specific Function:
Nuclear hormone receptor. The steroid hormones and their receptors are involved in the regulation of eukaryotic gene expression and affect cellular proliferation and differentiation in target tissues. Ligand-dependent nuclear transactivation involves either direct homodimer binding to a palindromic estrogen response element (ERE) sequence or association with other DNA-binding transcription factors, such as AP-1/c-Jun, c-Fos, ATF-2, Sp1 and Sp3, to mediate ERE-independent signaling. Ligand binding induces a conformational change allowing subsequent or combinatorial association with multiprotein coactivator complexes through LXXLL motifs of their respective components. Mutual transrepression occurs between the estrogen receptor (ER) and NF-kappa-B in a cell-type specific manner. Decreases NF-kappa-B DNA-binding activity and inhibits NF-kappa-B-mediated transcription from the IL6 promoter and displace RELA/p65 and associated coregulators from the promoter. Recruited to the NF-kappa-B response element of the CCL2 and IL8 promoters and can displace CREBBP. Present with NF-kappa-B components RELA/p65 and NFKB1/p50 on ERE sequences. Can also act synergistically with NF-kappa-B to activate transcription involving respective recruitment adjacent response elements; the function involves CREBBP. Can activate the transcriptional activity of TFF1. Also mediates membrane-initiated estrogen signaling involving various kinase cascades. Isoform 3 is involved in activation of NOS3 and endothelial nitric oxide production. Isoforms lacking one or several functional domains are thought to modulate transcriptional activity by competitive ligand or DNA binding and/or heterodimerization with the full length receptor. Essential for MTA1-mediated transcriptional regulation of BRCA1 and BCAS3. Isoform 3 can bind to ERE and inhibit isoform 1.
Gene Name:
ESR1
Uniprot ID:
P03372
Molecular Weight:
66215.45 Da
Binding/Activity Constants
TypeValueAssay TypeAssay Source
AC500.10 uMACEA_T47D_80hr_PositiveACEA Biosciences
AC501.37 uMNVS_NR_hERNovascreen
AC503.70 uMOT_ER_ERaERa_0480Odyssey Thera
AC503.71 uMOT_ER_ERaERa_1440Odyssey Thera
AC501.78 uMOT_ERa_EREGFP_0120Odyssey Thera
AC502.11 uMOT_ERa_EREGFP_0480Odyssey Thera
AC502.98 uMTox21_ERa_BLA_Antagonist_ratioTox21/NCGC
References
  1. Sipes NS, Martin MT, Kothiya P, Reif DM, Judson RS, Richard AM, Houck KA, Dix DJ, Kavlock RJ, Knudsen TB: Profiling 976 ToxCast chemicals across 331 enzymatic and receptor signaling assays. Chem Res Toxicol. 2013 Jun 17;26(6):878-95. doi: 10.1021/tx400021f. Epub 2013 May 16. [23611293 ]
Target Details
10. Estrogen receptor beta
General Function:
Zinc ion binding
Specific Function:
Nuclear hormone receptor. Binds estrogens with an affinity similar to that of ESR1, and activates expression of reporter genes containing estrogen response elements (ERE) in an estrogen-dependent manner (PubMed:20074560). Isoform beta-cx lacks ligand binding ability and has no or only very low ere binding activity resulting in the loss of ligand-dependent transactivation ability. DNA-binding by ESR1 and ESR2 is rapidly lost at 37 degrees Celsius in the absence of ligand while in the presence of 17 beta-estradiol and 4-hydroxy-tamoxifen loss in DNA-binding at elevated temperature is more gradual.
Gene Name:
ESR2
Uniprot ID:
Q92731
Molecular Weight:
59215.765 Da
Binding/Activity Constants
TypeValueAssay TypeAssay Source
AC501.59 uMOT_ER_ERaERb_0480Odyssey Thera
AC501.98 uMOT_ER_ERaERb_1440Odyssey Thera
AC500.17 uMOT_ER_ERbERb_0480Odyssey Thera
AC500.20 uMOT_ER_ERbERb_1440Odyssey Thera
References
  1. Sipes NS, Martin MT, Kothiya P, Reif DM, Judson RS, Richard AM, Houck KA, Dix DJ, Kavlock RJ, Knudsen TB: Profiling 976 ToxCast chemicals across 331 enzymatic and receptor signaling assays. Chem Res Toxicol. 2013 Jun 17;26(6):878-95. doi: 10.1021/tx400021f. Epub 2013 May 16. [23611293 ]
Target Details
11. Peroxisome proliferator-activated receptor gamma
General Function:
Zinc ion binding
Specific Function:
Nuclear receptor that binds peroxisome proliferators such as hypolipidemic drugs and fatty acids. Once activated by a ligand, the nuclear receptor binds to DNA specific PPAR response elements (PPRE) and modulates the transcription of its target genes, such as acyl-CoA oxidase. It therefore controls the peroxisomal beta-oxidation pathway of fatty acids. Key regulator of adipocyte differentiation and glucose homeostasis. ARF6 acts as a key regulator of the tissue-specific adipocyte P2 (aP2) enhancer. Acts as a critical regulator of gut homeostasis by suppressing NF-kappa-B-mediated proinflammatory responses. Plays a role in the regulation of cardiovascular circadian rhythms by regulating the transcription of ARNTL/BMAL1 in the blood vessels (By similarity).
Gene Name:
PPARG
Uniprot ID:
P37231
Molecular Weight:
57619.58 Da
Binding/Activity Constants
TypeValueAssay TypeAssay Source
AC500.37 uMATG_PPARg_TRANSAttagene
AC504.76 uMNVS_NR_hPPARgNovascreen
References
  1. Sipes NS, Martin MT, Kothiya P, Reif DM, Judson RS, Richard AM, Houck KA, Dix DJ, Kavlock RJ, Knudsen TB: Profiling 976 ToxCast chemicals across 331 enzymatic and receptor signaling assays. Chem Res Toxicol. 2013 Jun 17;26(6):878-95. doi: 10.1021/tx400021f. Epub 2013 May 16. [23611293 ]
Target Details
12. Mu-type opioid receptor
General Function:
Voltage-gated calcium channel activity
Specific Function:
Receptor for endogenous opioids such as beta-endorphin and endomorphin. Receptor for natural and synthetic opioids including morphine, heroin, DAMGO, fentanyl, etorphine, buprenorphin and methadone. Agonist binding to the receptor induces coupling to an inactive GDP-bound heterotrimeric G-protein complex and subsequent exchange of GDP for GTP in the G-protein alpha subunit leading to dissociation of the G-protein complex with the free GTP-bound G-protein alpha and the G-protein beta-gamma dimer activating downstream cellular effectors. The agonist- and cell type-specific activity is predominantly coupled to pertussis toxin-sensitive G(i) and G(o) G alpha proteins, GNAI1, GNAI2, GNAI3 and GNAO1 isoforms Alpha-1 and Alpha-2, and to a lesser extend to pertussis toxin-insensitive G alpha proteins GNAZ and GNA15. They mediate an array of downstream cellular responses, including inhibition of adenylate cyclase activity and both N-type and L-type calcium channels, activation of inward rectifying potassium channels, mitogen-activated protein kinase (MAPK), phospholipase C (PLC), phosphoinositide/protein kinase (PKC), phosphoinositide 3-kinase (PI3K) and regulation of NF-kappa-B. Also couples to adenylate cyclase stimulatory G alpha proteins. The selective temporal coupling to G-proteins and subsequent signaling can be regulated by RGSZ proteins, such as RGS9, RGS17 and RGS4. Phosphorylation by members of the GPRK subfamily of Ser/Thr protein kinases and association with beta-arrestins is involved in short-term receptor desensitization. Beta-arrestins associate with the GPRK-phosphorylated receptor and uncouple it from the G-protein thus terminating signal transduction. The phosphorylated receptor is internalized through endocytosis via clathrin-coated pits which involves beta-arrestins. The activation of the ERK pathway occurs either in a G-protein-dependent or a beta-arrestin-dependent manner and is regulated by agonist-specific receptor phosphorylation. Acts as a class A G-protein coupled receptor (GPCR) which dissociates from beta-arrestin at or near the plasma membrane and undergoes rapid recycling. Receptor down-regulation pathways are varying with the agonist and occur dependent or independent of G-protein coupling. Endogenous ligands induce rapid desensitization, endocytosis and recycling whereas morphine induces only low desensitization and endocytosis. Heterooligomerization with other GPCRs can modulate agonist binding, signaling and trafficking properties. Involved in neurogenesis. Isoform 12 couples to GNAS and is proposed to be involved in excitatory effects. Isoform 16 and isoform 17 do not bind agonists but may act through oligomerization with binding-competent OPRM1 isoforms and reduce their ligand binding activity.
Gene Name:
OPRM1
Uniprot ID:
P35372
Molecular Weight:
44778.855 Da
Binding/Activity Constants
TypeValueAssay TypeAssay Source
AC500.60 uMNVS_GPCR_hOpiate_muNovascreen
References
  1. Sipes NS, Martin MT, Kothiya P, Reif DM, Judson RS, Richard AM, Houck KA, Dix DJ, Kavlock RJ, Knudsen TB: Profiling 976 ToxCast chemicals across 331 enzymatic and receptor signaling assays. Chem Res Toxicol. 2013 Jun 17;26(6):878-95. doi: 10.1021/tx400021f. Epub 2013 May 16. [23611293 ]
Target Details
13. Retinoic acid receptor RXR-alpha
General Function:
Zinc ion binding
Specific Function:
Receptor for retinoic acid. Retinoic acid receptors bind as heterodimers to their target response elements in response to their ligands, all-trans or 9-cis retinoic acid, and regulate gene expression in various biological processes. The RAR/RXR heterodimers bind to the retinoic acid response elements (RARE) composed of tandem 5'-AGGTCA-3' sites known as DR1-DR5. The high affinity ligand for RXRs is 9-cis retinoic acid. RXRA serves as a common heterodimeric partner for a number of nuclear receptors. The RXR/RAR heterodimers bind to the retinoic acid response elements (RARE) composed of tandem 5'-AGGTCA-3' sites known as DR1-DR5. In the absence of ligand, the RXR-RAR heterodimers associate with a multiprotein complex containing transcription corepressors that induce histone acetylation, chromatin condensation and transcriptional suppression. On ligand binding, the corepressors dissociate from the receptors and associate with the coactivators leading to transcriptional activation. The RXRA/PPARA heterodimer is required for PPARA transcriptional activity on fatty acid oxidation genes such as ACOX1 and the P450 system genes.
Gene Name:
RXRA
Uniprot ID:
P19793
Molecular Weight:
50810.835 Da
Binding/Activity Constants
TypeValueAssay TypeAssay Source
AC500.99 uMOT_NURR1_NURR1RXRa_1440Odyssey Thera
References
  1. Sipes NS, Martin MT, Kothiya P, Reif DM, Judson RS, Richard AM, Houck KA, Dix DJ, Kavlock RJ, Knudsen TB: Profiling 976 ToxCast chemicals across 331 enzymatic and receptor signaling assays. Chem Res Toxicol. 2013 Jun 17;26(6):878-95. doi: 10.1021/tx400021f. Epub 2013 May 16. [23611293 ]
Target Details
14. Neutrophil elastase
General Function:
Serine-type endopeptidase activity
Specific Function:
Modifies the functions of natural killer cells, monocytes and granulocytes. Inhibits C5a-dependent neutrophil enzyme release and chemotaxis.
Gene Name:
ELANE
Uniprot ID:
P08246
Molecular Weight:
28517.81 Da
Binding/Activity Constants
TypeValueAssay TypeAssay Source
AC502.16 uMNVS_ENZ_hElastaseNovascreen
References
  1. Sipes NS, Martin MT, Kothiya P, Reif DM, Judson RS, Richard AM, Houck KA, Dix DJ, Kavlock RJ, Knudsen TB: Profiling 976 ToxCast chemicals across 331 enzymatic and receptor signaling assays. Chem Res Toxicol. 2013 Jun 17;26(6):878-95. doi: 10.1021/tx400021f. Epub 2013 May 16. [23611293 ]
Target Details
15. Bile acid receptor
General Function:
Zinc ion binding
Specific Function:
Ligand-activated transcription factor. Receptor for bile acids such as chenodeoxycholic acid, lithocholic acid and deoxycholic acid. Represses the transcription of the cholesterol 7-alpha-hydroxylase gene (CYP7A1) through the induction of NR0B2 or FGF19 expression, via two distinct mechanisms. Activates the intestinal bile acid-binding protein (IBABP). Activates the transcription of bile salt export pump ABCB11 by directly recruiting histone methyltransferase CARM1 to this locus.
Gene Name:
NR1H4
Uniprot ID:
Q96RI1
Molecular Weight:
55913.915 Da
Binding/Activity Constants
TypeValueAssay TypeAssay Source
AC503.26 uMOT_SRC1_SRC1FXR_0480Odyssey Thera
AC508.60 uMOT_SRC1_SRC1FXR_1440Odyssey Thera
References
  1. Sipes NS, Martin MT, Kothiya P, Reif DM, Judson RS, Richard AM, Houck KA, Dix DJ, Kavlock RJ, Knudsen TB: Profiling 976 ToxCast chemicals across 331 enzymatic and receptor signaling assays. Chem Res Toxicol. 2013 Jun 17;26(6):878-95. doi: 10.1021/tx400021f. Epub 2013 May 16. [23611293 ]
Target Details
16. Cytochrome P450 2C19
General Function:
Steroid hydroxylase activity
Specific Function:
Responsible for the metabolism of a number of therapeutic agents such as the anticonvulsant drug S-mephenytoin, omeprazole, proguanil, certain barbiturates, diazepam, propranolol, citalopram and imipramine.
Gene Name:
CYP2C19
Uniprot ID:
P33261
Molecular Weight:
55930.545 Da
Binding/Activity Constants
TypeValueAssay TypeAssay Source
AC503.67 uMNVS_ADME_hCYP2C19Novascreen
References
  1. Sipes NS, Martin MT, Kothiya P, Reif DM, Judson RS, Richard AM, Houck KA, Dix DJ, Kavlock RJ, Knudsen TB: Profiling 976 ToxCast chemicals across 331 enzymatic and receptor signaling assays. Chem Res Toxicol. 2013 Jun 17;26(6):878-95. doi: 10.1021/tx400021f. Epub 2013 May 16. [23611293 ]
Target Details
17. Cholinesterase
General Function:
Identical protein binding
Specific Function:
Esterase with broad substrate specificity. Contributes to the inactivation of the neurotransmitter acetylcholine. Can degrade neurotoxic organophosphate esters.
Gene Name:
BCHE
Uniprot ID:
P06276
Molecular Weight:
68417.575 Da
Binding/Activity Constants
TypeValueAssay TypeAssay Source
AC503.93 uMNVS_ENZ_hESNovascreen
References
  1. Sipes NS, Martin MT, Kothiya P, Reif DM, Judson RS, Richard AM, Houck KA, Dix DJ, Kavlock RJ, Knudsen TB: Profiling 976 ToxCast chemicals across 331 enzymatic and receptor signaling assays. Chem Res Toxicol. 2013 Jun 17;26(6):878-95. doi: 10.1021/tx400021f. Epub 2013 May 16. [23611293 ]
Target Details
18. Cytochrome P450 2C9
General Function:
Steroid hydroxylase activity
Specific Function:
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally unrelated compounds, including steroids, fatty acids, and xenobiotics. This enzyme contributes to the wide pharmacokinetics variability of the metabolism of drugs such as S-warfarin, diclofenac, phenytoin, tolbutamide and losartan.
Gene Name:
CYP2C9
Uniprot ID:
P11712
Molecular Weight:
55627.365 Da
Binding/Activity Constants
TypeValueAssay TypeAssay Source
AC504.20 uMNVS_ADME_hCYP2C9Novascreen
References
  1. Sipes NS, Martin MT, Kothiya P, Reif DM, Judson RS, Richard AM, Houck KA, Dix DJ, Kavlock RJ, Knudsen TB: Profiling 976 ToxCast chemicals across 331 enzymatic and receptor signaling assays. Chem Res Toxicol. 2013 Jun 17;26(6):878-95. doi: 10.1021/tx400021f. Epub 2013 May 16. [23611293 ]
Target Details
19. Cytochrome P450 3A4
General Function:
Vitamin d3 25-hydroxylase activity
Specific Function:
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It performs a variety of oxidation reactions (e.g. caffeine 8-oxidation, omeprazole sulphoxidation, midazolam 1'-hydroxylation and midazolam 4-hydroxylation) of structurally unrelated compounds, including steroids, fatty acids, and xenobiotics. Acts as a 1,8-cineole 2-exo-monooxygenase. The enzyme also hydroxylates etoposide (PubMed:11159812). Catalyzes 4-beta-hydroxylation of cholesterol. May catalyze 25-hydroxylation of cholesterol in vitro (PubMed:21576599).
Gene Name:
CYP3A4
Uniprot ID:
P08684
Molecular Weight:
57342.67 Da
Binding/Activity Constants
TypeValueAssay TypeAssay Source
AC504.79 uMNVS_ADME_hCYP3A4Novascreen
References
  1. Sipes NS, Martin MT, Kothiya P, Reif DM, Judson RS, Richard AM, Houck KA, Dix DJ, Kavlock RJ, Knudsen TB: Profiling 976 ToxCast chemicals across 331 enzymatic and receptor signaling assays. Chem Res Toxicol. 2013 Jun 17;26(6):878-95. doi: 10.1021/tx400021f. Epub 2013 May 16. [23611293 ]
Target Details
20. Vitamin D3 receptor
General Function:
Zinc ion binding
Specific Function:
Nuclear hormone receptor. Transcription factor that mediates the action of vitamin D3 by controlling the expression of hormone sensitive genes. Recruited to promoters via its interaction with BAZ1B/WSTF which mediates the interaction with acetylated histones, an essential step for VDR-promoter association. Plays a central role in calcium homeostasis.
Gene Name:
VDR
Uniprot ID:
P11473
Molecular Weight:
48288.64 Da
Binding/Activity Constants
TypeValueAssay TypeAssay Source
AC507.67 uMATG_VDRE_CISAttagene
References
  1. Sipes NS, Martin MT, Kothiya P, Reif DM, Judson RS, Richard AM, Houck KA, Dix DJ, Kavlock RJ, Knudsen TB: Profiling 976 ToxCast chemicals across 331 enzymatic and receptor signaling assays. Chem Res Toxicol. 2013 Jun 17;26(6):878-95. doi: 10.1021/tx400021f. Epub 2013 May 16. [23611293 ]
Target Details
21. Hypoxia-inducible factor 1-alpha
General Function:
Ubiquitin protein ligase binding
Specific Function:
Functions as a master transcriptional regulator of the adaptive response to hypoxia. Under hypoxic conditions, activates the transcription of over 40 genes, including erythropoietin, glucose transporters, glycolytic enzymes, vascular endothelial growth factor, HILPDA, and other genes whose protein products increase oxygen delivery or facilitate metabolic adaptation to hypoxia. Plays an essential role in embryonic vascularization, tumor angiogenesis and pathophysiology of ischemic disease. Binds to core DNA sequence 5'-[AG]CGTG-3' within the hypoxia response element (HRE) of target gene promoters. Activation requires recruitment of transcriptional coactivators such as CREBPB and EP300. Activity is enhanced by interaction with both, NCOA1 or NCOA2. Interaction with redox regulatory protein APEX seems to activate CTAD and potentiates activation by NCOA1 and CREBBP. Involved in the axonal distribution and transport of mitochondria in neurons during hypoxia.
Gene Name:
HIF1A
Uniprot ID:
Q16665
Molecular Weight:
92669.595 Da
Binding/Activity Constants
TypeValueAssay TypeAssay Source
AC508.26 uMATG_HIF1a_CISAttagene
References
  1. Sipes NS, Martin MT, Kothiya P, Reif DM, Judson RS, Richard AM, Houck KA, Dix DJ, Kavlock RJ, Knudsen TB: Profiling 976 ToxCast chemicals across 331 enzymatic and receptor signaling assays. Chem Res Toxicol. 2013 Jun 17;26(6):878-95. doi: 10.1021/tx400021f. Epub 2013 May 16. [23611293 ]
Target Details
22. Nuclear receptor ROR-gamma
General Function:
Zinc ion binding
Specific Function:
Nuclear receptor that binds DNA as a monomer to ROR response elements (RORE) containing a single core motif half-site 5'-AGGTCA-3' preceded by a short A-T-rich sequence. Key regulator of cellular differentiation, immunity, peripheral circadian rhythm as well as lipid, steroid, xenobiotics and glucose metabolism. Considered to have intrinsic transcriptional activity, have some natural ligands like oxysterols that act as agonists (25-hydroxycholesterol) or inverse agonists (7-oxygenated sterols), enhancing or repressing the transcriptional activity, respectively. Recruits distinct combinations of cofactors to target gene regulatory regions to modulate their transcriptional expression, depending on the tissue, time and promoter contexts. Regulates the circadian expression of clock genes such as CRY1, ARNTL/BMAL1 and NR1D1 in peripheral tissues and in a tissue-selective manner. Competes with NR1D1 for binding to their shared DNA response element on some clock genes such as ARNTL/BMAL1, CRY1 and NR1D1 itself, resulting in NR1D1-mediated repression or RORC-mediated activation of the expression, leading to the circadian pattern of clock genes expression. Therefore influences the period length and stability of the clock. Involved in the regulation of the rhythmic expression of genes involved in glucose and lipid metabolism, including PLIN2 and AVPR1A. Negative regulator of adipocyte differentiation through the regulation of early phase genes expression, such as MMP3. Controls adipogenesis as well as adipocyte size and modulates insulin sensitivity in obesity. In liver, has specific and redundant functions with RORA as positive or negative modulator of expression of genes encoding phase I and Phase II proteins involved in the metabolism of lipids, steroids and xenobiotics, such as SULT1E1. Also plays also a role in the regulation of hepatocyte glucose metabolism through the regulation of G6PC and PCK1. Regulates the rhythmic expression of PROX1 and promotes its nuclear localization (By similarity). Plays an indispensable role in the induction of IFN-gamma dependent anti-mycobacterial systemic immunity (PubMed:26160376).Isoform 2: Essential for thymopoiesis and the development of several secondary lymphoid tissues, including lymph nodes and Peyer's patches. Required for the generation of LTi (lymphoid tissue inducer) cells. Regulates thymocyte survival through DNA-binding on ROREs of target gene promoter regions and recruitment of coactivaros via the AF-2. Also plays a key role, downstream of IL6 and TGFB and synergistically with RORA, for lineage specification of uncommitted CD4(+) T-helper (T(H)) cells into T(H)17 cells, antagonizing the T(H)1 program. Probably regulates IL17 and IL17F expression on T(H) by binding to the essential enhancer conserved non-coding sequence 2 (CNS2) in the IL17-IL17F locus. May also play a role in the pre-TCR activation cascade leading to the maturation of alpha/beta T-cells and may participate in the regulation of DNA accessibility in the TCR-J(alpha) locus.
Gene Name:
RORC
Uniprot ID:
P51449
Molecular Weight:
58194.845 Da
Binding/Activity Constants
TypeValueAssay TypeAssay Source
AC508.78 uMATG_RORE_CISAttagene
References
  1. Sipes NS, Martin MT, Kothiya P, Reif DM, Judson RS, Richard AM, Houck KA, Dix DJ, Kavlock RJ, Knudsen TB: Profiling 976 ToxCast chemicals across 331 enzymatic and receptor signaling assays. Chem Res Toxicol. 2013 Jun 17;26(6):878-95. doi: 10.1021/tx400021f. Epub 2013 May 16. [23611293 ]
Target Details
23. Aryl hydrocarbon receptor
General Function:
Transcription regulatory region dna binding
Specific Function:
Ligand-activated transcriptional activator. Binds to the XRE promoter region of genes it activates. Activates the expression of multiple phase I and II xenobiotic chemical metabolizing enzyme genes (such as the CYP1A1 gene). Mediates biochemical and toxic effects of halogenated aromatic hydrocarbons. Involved in cell-cycle regulation. Likely to play an important role in the development and maturation of many tissues. Regulates the circadian clock by inhibiting the basal and circadian expression of the core circadian component PER1. Inhibits PER1 by repressing the CLOCK-ARNTL/BMAL1 heterodimer mediated transcriptional activation of PER1.
Gene Name:
AHR
Uniprot ID:
P35869
Molecular Weight:
96146.705 Da
Binding/Activity Constants
TypeValueAssay TypeAssay Source
AC509.45 uMATG_Ahr_CISAttagene
References
  1. Sipes NS, Martin MT, Kothiya P, Reif DM, Judson RS, Richard AM, Houck KA, Dix DJ, Kavlock RJ, Knudsen TB: Profiling 976 ToxCast chemicals across 331 enzymatic and receptor signaling assays. Chem Res Toxicol. 2013 Jun 17;26(6):878-95. doi: 10.1021/tx400021f. Epub 2013 May 16. [23611293 ]