Target Information
| Target General Information | Top | |||||
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| Target ID |
T46521
(Former ID: TTDC00332)
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| Target Name |
Androgen receptor messenger RNA (AR mRNA)
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| Synonyms |
Testosterone receptor (mRNA); Nuclear receptor subfamily 3 group C member 4 (mRNA); NR3C4 (mRNA); Dihydrotestosterone receptor (mRNA); DHTR (mRNA); Androgen receptor (mRNA)
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| Gene Name |
AR
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| Target Type |
Clinical trial target
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[1] | ||||
| Disease | [+] 1 Target-related Diseases | + | ||||
| 1 | Prostate hyperplasia [ICD-11: GA90] | |||||
| Function |
Transcription factor activity is modulated by bound coactivator and corepressor proteins like ZBTB7A that recruits NCOR1 and NCOR2 to the androgen response elements/ARE on target genes, negatively regulating androgen receptor signaling and androgen-induced cell proliferation. Transcription activation is also down-regulated by NR0B2. Activated, but not phosphorylated, by HIPK3 and ZIPK/DAPK3. Steroid hormone receptors are ligand-activated transcription factors that regulate eukaryotic gene expression and affect cellular proliferation and differentiation in target tissues.
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| BioChemical Class |
mRNA target
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| UniProt ID | ||||||
| Sequence |
MEVQLGLGRVYPRPPSKTYRGAFQNLFQSVREVIQNPGPRHPEAASAAPPGASLLLLQQQ
QQQQQQQQQQQQQQQQQQQQETSPRQQQQQQGEDGSPQAHRRGPTGYLVLDEEQQPSQPQ SALECHPERGCVPEPGAAVAASKGLPQQLPAPPDEDDSAAPSTLSLLGPTFPGLSSCSAD LKDILSEASTMQLLQQQQQEAVSEGSSSGRAREASGAPTSSKDNYLGGTSTISDNAKELC KAVSVSMGLGVEALEHLSPGEQLRGDCMYAPLLGVPPAVRPTPCAPLAECKGSLLDDSAG KSTEDTAEYSPFKGGYTKGLEGESLGCSGSAAAGSSGTLELPSTLSLYKSGALDEAAAYQ SRDYYNFPLALAGPPPPPPPPHPHARIKLENPLDYGSAWAAAAAQCRYGDLASLHGAGAA GPGSGSPSAAASSSWHTLFTAEEGQLYGPCGGGGGGGGGGGGGGGGGGGGGGGEAGAVAP YGYTRPPQGLAGQESDFTAPDVWYPGGMVSRVPYPSPTCVKSEMGPWMDSYSGPYGDMRL ETARDHVLPIDYYFPPQKTCLICGDEASGCHYGALTCGSCKVFFKRAAEGKQKYLCASRN DCTIDKFRRKNCPSCRLRKCYEAGMTLGARKLKKLGNLKLQEEGEASSTTSPTEETTQKL TVSHIEGYECQPIFLNVLEAIEPGVVCAGHDNNQPDSFAALLSSLNELGERQLVHVVKWA KALPGFRNLHVDDQMAVIQYSWMGLMVFAMGWRSFTNVNSRMLYFAPDLVFNEYRMHKSR MYSQCVRMRHLSQEFGWLQITPQEFLCMKALLLFSIIPVDGLKNQKFFDELRMNYIKELD RIIACKRKNPTSCSRRFYQLTKLLDSVQPIARELHQFTFDLLIKSHMVSVDFPEMMAEII SVQVPKILSGKVKPIYFHTQ Click to Show/Hide
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| Drugs and Modes of Action | Top | |||||
|---|---|---|---|---|---|---|
| Approved Drug(s) | [+] 1 Approved Drugs | + | ||||
| 1 | Dihydrotestosterone | Drug Info | Phase 4 | Prostate hyperplasia | [2], [3] | |
| Clinical Trial Drug(s) | [+] 4 Clinical Trial Drugs | + | ||||
| 1 | BAY 86-5044 | Drug Info | Phase 2 | Breast cancer | [4] | |
| 2 | TRC-253 | Drug Info | Phase 1/2 | Prostate cancer | [6] | |
| 3 | EZN-4176 | Drug Info | Phase 1 | Prostate cancer | [7] | |
| 4 | ISIS-AR | Drug Info | Phase 1 | Prostate cancer | [8] | |
| Discontinued Drug(s) | [+] 1 Discontinued Drugs | + | ||||
| 1 | RU-58841 | Drug Info | Discontinued in Phase 1 | Acne vulgaris | [9] | |
| Mode of Action | [+] 3 Modes of Action | + | ||||
| Agonist | [+] 4 Agonist drugs | + | ||||
| 1 | Dihydrotestosterone | Drug Info | [1] | |||
| 2 | andarine | Drug Info | [22] | |||
| 3 | [3H]methyltrienolone | Drug Info | [1] | |||
| 4 | [3H]mibolerone | Drug Info | [1] | |||
| Inhibitor | [+] 51 Inhibitor drugs | + | ||||
| 1 | BAY 86-5044 | Drug Info | [10] | |||
| 2 | EUGENOL | Drug Info | [13] | |||
| 3 | RU-58841 | Drug Info | [14] | |||
| 4 | 1,2-dibromo-4-(1,2-dibromoethyl)cyclohexane | Drug Info | [15] | |||
| 5 | 2'-Hydroxy-3-methoxy-biphenyl-4-carbonitrile | Drug Info | [14] | |||
| 6 | 2-chloro-4-(o-tolyloxy)benzonitrile | Drug Info | [16] | |||
| 7 | 2-methoxy-4-(2-methoxyphenylthio)benzonitrile | Drug Info | [17] | |||
| 8 | 2-methoxy-4-(m-tolyloxy)benzonitrile | Drug Info | [17] | |||
| 9 | 2-methoxy-4-(o-tolyloxy)benzonitrile | Drug Info | [17] | |||
| 10 | 2-methoxy-4-(p-tolyloxy)benzonitrile | Drug Info | [17] | |||
| 11 | 2-methoxy-4-(propylthio)benzonitrile | Drug Info | [17] | |||
| 12 | 3,2'-bis-trifluoromethyl-biphenyl-4-carbonitrile | Drug Info | [18] | |||
| 13 | 3-chloro-4-(o-tolyloxy)benzonitrile | Drug Info | [16] | |||
| 14 | 3-chloro-4-(o-tolylthio)benzonitrile | Drug Info | [17] | |||
| 15 | 3-methoxy-4-(m-tolyloxy)benzonitrile | Drug Info | [17] | |||
| 16 | 3-methoxy-4-(o-tolyloxy)benzonitrile | Drug Info | [17] | |||
| 17 | 3-methoxy-4-(p-tolyloxy)benzonitrile | Drug Info | [17] | |||
| 18 | 4-(2,6-dimethylphenylthio)-2-methoxybenzonitrile | Drug Info | [17] | |||
| 19 | 4-(butylthio)-2-(trifluoromethyl)benzonitrile | Drug Info | [17] | |||
| 20 | 4-(butylthio)-2-methoxybenzonitrile | Drug Info | [17] | |||
| 21 | 4-(cyclobutylmethylthio)-2-methoxybenzonitrile | Drug Info | [17] | |||
| 22 | 4-(cyclopropylmethylthio)-2-methoxybenzonitrile | Drug Info | [17] | |||
| 23 | 4-(isopentylthio)-2-methoxybenzonitrile | Drug Info | [17] | |||
| 24 | 4-(isopropylthio)-2-(trifluoromethyl)benzonitrile | Drug Info | [17] | |||
| 25 | 4-(isopropylthio)-2-methoxybenzonitrile | Drug Info | [17] | |||
| 26 | 4-(m-tolyloxy)-2-(trifluoromethyl)benzonitrile | Drug Info | [16] | |||
| 27 | 4-(mesityloxy)-2-(trifluoromethyl)benzonitrile | Drug Info | [16] | |||
| 28 | 4-(mesitylthio)-2-(trifluoromethyl)benzonitrile | Drug Info | [17] | |||
| 29 | 4-(mesitylthio)-2-methoxybenzonitrile | Drug Info | [17] | |||
| 30 | 4-(o-tolyloxy)-2-(trifluoromethyl)benzonitrile | Drug Info | [16] | |||
| 31 | 4-(p-tolyloxy)-2-(trifluoromethyl)benzonitrile | Drug Info | [16] | |||
| 32 | 4-(propylthio)-2-(trifluoromethyl)benzonitrile | Drug Info | [17] | |||
| 33 | 6-amino-4-trifluoromethylquinolin-2(1H)-one | Drug Info | [19] | |||
| 34 | 6-Hydroxyflavanone | Drug Info | [20] | |||
| 35 | 6-N-propyl -4-trifluoromethylquinolin-2(1H)-one | Drug Info | [19] | |||
| 36 | AL-43 | Drug Info | [21] | |||
| 37 | APIGENIN | Drug Info | [20] | |||
| 38 | BMS-564929 | Drug Info | [24] | |||
| 39 | CP-394531 | Drug Info | [25] | |||
| 40 | CP-409069 | Drug Info | [25] | |||
| 41 | flavone | Drug Info | [20] | |||
| 42 | KAEMPFEROL | Drug Info | [20] | |||
| 43 | LG-120838 | Drug Info | [26] | |||
| 44 | LG-121071 | Drug Info | [27] | |||
| 45 | LGD-2226 | Drug Info | [28] | |||
| 46 | LGD-5552 | Drug Info | [29] | |||
| 47 | NSC-26745 | Drug Info | [20] | |||
| 48 | PF-0998425 | Drug Info | [14] | |||
| 49 | RU-43044 | Drug Info | [25] | |||
| 50 | RU-56187 | Drug Info | [30] | |||
| 51 | WAY-255348 | Drug Info | [31] | |||
| Antagonist | [+] 2 Antagonist drugs | + | ||||
| 1 | TRC-253 | Drug Info | [11] | |||
| 2 | bisphenol A | Drug Info | [23] | |||
| Cell-based Target Expression Variations | Top | |||||
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| Cell-based Target Expression Variations | ||||||
| Drug Property Profile of Target | Top | |
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| (1) Molecular Weight (mw) based Drug Clustering | (2) Octanol/Water Partition Coefficient (xlogp) based Drug Clustering | |
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| (3) Hydrogen Bond Donor Count (hbonddonor) based Drug Clustering | (4) Hydrogen Bond Acceptor Count (hbondacc) based Drug Clustering | |
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| (5) Rotatable Bond Count (rotbonds) based Drug Clustering | (6) Topological Polar Surface Area (polararea) based Drug Clustering | |
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| "RO5" indicates the cutoff set by lipinski's rule of five; "D123AB" colored in GREEN denotes the no violation of any cutoff in lipinski's rule of five; "D123AB" colored in PURPLE refers to the violation of only one cutoff in lipinski's rule of five; "D123AB" colored in BLACK represents the violation of more than one cutoffs in lipinski's rule of five | ||
| Co-Targets | Top | |||||
|---|---|---|---|---|---|---|
| Co-Targets | ||||||
| Target Profiles in Patients | Top | |||||
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| Target Expression Profile (TEP) | ||||||
| Target Affiliated Biological Pathways | Top | |||||
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| KEGG Pathway | [+] 3 KEGG Pathways | + | ||||
| 1 | Oocyte meiosis | |||||
| 2 | Pathways in cancer | |||||
| 3 | Prostate cancer | |||||
| NetPath Pathway | [+] 3 NetPath Pathways | + | ||||
| 1 | EGFR1 Signaling Pathway | |||||
| 2 | AndrogenReceptor Signaling Pathway | |||||
| 3 | FSH Signaling Pathway | |||||
| PID Pathway | [+] 7 PID Pathways | + | ||||
| 1 | Regulation of nuclear SMAD2/3 signaling | |||||
| 2 | Coregulation of Androgen receptor activity | |||||
| 3 | Regulation of Androgen receptor activity | |||||
| 4 | Nongenotropic Androgen signaling | |||||
| 5 | Regulation of nuclear beta catenin signaling and target gene transcription | |||||
| 6 | FOXA1 transcription factor network | |||||
| 7 | Notch-mediated HES/HEY network | |||||
| Reactome | [+] 2 Reactome Pathways | + | ||||
| 1 | Nuclear Receptor transcription pathway | |||||
| 2 | Activated PKN1 stimulates transcription of AR (androgen receptor) regulated genes KLK2 and KLK3 | |||||
| WikiPathways | [+] 6 WikiPathways | + | ||||
| 1 | SIDS Susceptibility Pathways | |||||
| 2 | Integrated Pancreatic Cancer Pathway | |||||
| 3 | Prostate Cancer | |||||
| 4 | Integrated Breast Cancer Pathway | |||||
| 5 | Nuclear Receptors | |||||
| 6 | Androgen receptor signaling pathway | |||||
| Target-Related Models and Studies | Top | |||||
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| Target Validation | ||||||
| References | Top | |||||
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| REF 1 | URL: http://www.guidetopharmacology.org Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Target id: 628). | |||||
| REF 2 | URL: http://www.guidetopharmacology.org Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 2856). | |||||
| REF 3 | ClinicalTrials.gov (NCT00062790) Effect Of Dutasteride On Intraprostatic Dihydrotestosterone (DHT) Levels. U.S. National Institutes of Health. | |||||
| REF 4 | ClinicalTrials.gov (NCT00555919) ZK 230211 in Postmenopausal Woman With Metastatic Breast Cancer. U.S. National Institutes of Health. | |||||
| REF 5 | ClinicalTrials.gov (NCT03300505) ARRO-CITO: (UMCC 2017.055) Phase Ib/II Single-Arm Multi-Center Study of IONIS-AR-2.5Rx, a Next Generation Androgen Receptor Antisense Oligonucleotide, in Combination With Enzalutamide in Metastatic Castration Resistant Prostate Cancer. U.S.National Institutes of Health. | |||||
| REF 6 | ClinicalTrials.gov (NCT02987829) Phase 1/2A Study of TRC253, an Androgen Receptor Antagonist, in Metastatic Castration-resistant Prostate Cancer Patients. U.S. National Institutes of Health. | |||||
| REF 7 | 2011 Pipeline of Santaris Pharma. | |||||
| REF 8 | Clinical pipeline report, company report or official report of ISIS Pharmaceuticals. | |||||
| REF 9 | Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800005990) | |||||
| REF 10 | Synthesis and biological activity of a novel, highly potent progesterone receptor antagonist. J Med Chem. 2000 Dec 28;43(26):5010-6. | |||||
| REF 11 | Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA) | |||||
| REF 12 | Clinical pipeline report, company report or official report of ISIS Pharmaceuticals. | |||||
| REF 13 | Effect of essential oils, such as raspberry ketone and its derivatives, on antiandrogenic activity based on in vitro reporter gene assay. Bioorg Med Chem Lett. 2010 Apr 1;20(7):2111-4. | |||||
| REF 14 | Rational design and synthesis of 4-((1R,2R)-2-hydroxycyclohexyl)-2(trifluoromethyl)benzonitrile (PF-998425), a novel, nonsteroidal androgen recepto... J Med Chem. 2008 Nov 13;51(21):7010-4. | |||||
| REF 15 | Identification of the brominated flame retardant 1,2-dibromo-4-(1,2-dibromoethyl)cyclohexane as an androgen agonist. J Med Chem. 2006 Dec 14;49(25):7366-72. | |||||
| REF 16 | Diphenyl ethers as androgen receptor antagonists for the topical suppression of sebum production. Bioorg Med Chem Lett. 2009 Apr 15;19(8):2176-8. | |||||
| REF 17 | 4-(Alkylthio)- and 4-(arylthio)-benzonitrile derivatives as androgen receptor antagonists for the topical suppression of sebum production. Bioorg Med Chem Lett. 2009 Mar 1;19(5):1310-3. | |||||
| REF 18 | Preparation of 4-aryl-2-trifluoromethylbenzonitrile derivatives as androgen receptor antagonists for topical suppression of sebum production. Bioorg Med Chem Lett. 2007 Oct 15;17(20):5529-32. | |||||
| REF 19 | Discovery of 6-N,N-bis(2,2,2-trifluoroethyl)amino- 4-trifluoromethylquinolin-2(1H)-one as a novel selective androgen receptor modulator. J Med Chem. 2006 Oct 19;49(21):6143-6. | |||||
| REF 20 | Effect of flavonoids on androgen and glucocorticoid receptors based on in vitro reporter gene assay. Bioorg Med Chem Lett. 2009 Aug 15;19(16):4706-10. | |||||
| REF 21 | Nonsteroidal selective glucocorticoid modulators: the effect of C-10 substitution on receptor selectivity and functional potency of 5-allyl-2,5-dih... J Med Chem. 2003 Mar 13;46(6):1016-30. | |||||
| REF 22 | Nonsteroidal selective androgen receptor modulators (SARMs): dissociating the anabolic and androgenic activities of the androgen receptor for therapeutic benefit. J Med Chem. 2009 Jun 25;52(12):3597-617. | |||||
| REF 23 | Structure-activity relationships of bisphenol A analogs at estrogen receptors (ERs): discovery of an ERalpha-selective antagonist. Bioorg Med Chem Lett. 2013 Jul 15;23(14):4031-6. | |||||
| REF 24 | N-aryl-oxazolidin-2-imine muscle selective androgen receptor modulators enhance potency through pharmacophore reorientation. J Med Chem. 2009 May 14;52(9):2794-8. | |||||
| REF 25 | Discovery of potent, nonsteroidal, and highly selective glucocorticoid receptor antagonists. J Med Chem. 2002 Jun 6;45(12):2417-24. | |||||
| REF 26 | 5-Benzylidene 1,2-dihydrochromeno[3,4-f]quinolines, a novel class of nonsteroidal human progesterone receptor agonists. J Med Chem. 1998 Oct 22;41(22):4354-9. | |||||
| REF 27 | Novel series of potent, nonsteroidal, selective androgen receptor modulators based on 7H-[1,4]oxazino[3,2-g]quinolin-7-ones. J Med Chem. 2007 May 17;50(10):2486-96. | |||||
| REF 28 | Novel selective androgen receptor modulators: SAR studies on 6-bisalkylamino-2-quinolinones. Bioorg Med Chem Lett. 2007 Mar 15;17(6):1527-31. | |||||
| REF 29 | Antiinflammatory glucocorticoid receptor ligand with reduced side effects exhibits an altered protein-protein interaction profile. Proc Natl Acad Sci U S A. 2007 Dec 4;104(49):19244-9. | |||||
| REF 30 | Structure-activity relationships of bioisosteric replacement of the carboxylic acid in novel androgen receptor pure antagonists. Bioorg Med Chem. 2010 May 1;18(9):3159-68. | |||||
| REF 31 | 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-... J Med Chem. 2008 Mar 27;51(6):1861-73. | |||||
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