Target Information

Target General Infomation
Target ID
T89041
Former ID
TTDS00241
Target Name
17 alpha-hydroxylase-C17, 20-lyase
Gene Name
CYP17A1
Synonyms
17 alpha-Hydroxylase/C17-20-lyase; CYP 17; CYPXVII; P450 17; P450-C17; P450c17; Steroid 17-alpha-hydroxylase/17,20 lyase; CYP17A1
Target Type
Successful
Disease Metastatic castration-resistant prostate cancer [ICD9: 140-229, 185; ICD10: C61]
Prostate cancer [ICD9: 185; ICD10: C61]
Function
Conversion of pregnenolone and progesterone to their 17- alpha-hydroxylated products and subsequently to dehydroepiandrosterone (DHEA) and androstenedione. Catalyzes both the 17-alpha-hydroxylation and the 17,20-lyase reaction. Involved in sexual development during fetal life and at puberty.
BioChemical Class
Oxidoreductases acting on paired donors
Target Validation
T89041
UniProt ID
P05093
EC Number
EC 4.1.2.30
Sequence
MWELVALLLLTLAYLFWPKRRCPGAKYPKSLLSLPLVGSLPFLPRHGHMHNNFFKLQKKY
GPIYSVRMGTKTTVIVGHHQLAKEVLIKKGKDFSGRPQMATLDIASNNRKGIAFADSGAH
WQLHRRLAMATFALFKDGDQKLEKIICQEISTLCDMLATHNGQSIDISFPVFVAVTNVIS
LICFNTSYKNGDPELNVIQNYNEGIIDNLSKDSLVDLVPWLKIFPNKTLEKLKSHVKIRN
DLLNKILENYKEKFRSDSITNMLDTLMQAKMNSDNGNAGPDQDSELLSDNHILTTIGDIF
GAGVETTTSVVKWTLAFLLHNPQVKKKLYEEIDQNVGFSRTPTISDRNRLLLLEATIREV
LRLRPVAPMLIPHKANVDSSIGEFAVDKGTEVIINLWALHHNEKEWHQPDQFMPERFLNP
AGTQLISPSVSYLPFGAGPRSCIGEILARQELFLIMAWLLQRFDLEVPDDGQLPSLEGIP
KVVFLIDSFKVKIKVRQAWREAQAEGST
Drugs and Mode of Action
Drug(s) ABIRATERONE Drug Info Approved Metastatic castration-resistant prostate cancer [527863], [531783], [541843]
Abiraterone acetate Drug Info Approved Metastatic castration-resistant prostate cancer [551871]
TAK-700 Drug Info Phase 3 Prostate cancer [531762]
CFG920 Drug Info Phase 1/2 Metastatic castration-resistant prostate cancer [532436]
Inhibitor 1-((9H-Fluoren-2-yl)ethyl)-1H-imidazole Drug Info [529625]
1-((9H-Fluoren-2-yl)methyl)-1H-imidazole Drug Info [529625]
1-(1-(4'-Ethylbiphenyl-4-yl)propyl)-1H-imidazole Drug Info [529625]
1-(1-(4-thiophen-3-yl-phenyl)propyl)-1Himidazole Drug Info [529201]
1-(1-(4-thiophen-3-ylphenyl)ethyl)-1H-imidazole Drug Info [529201]
1-(1-(Biphenyl-4-yl)allyl)-1H-imidazole Drug Info [529625]
1-(1-Biphenyl-4-yl-2-methyl-propyl)-1H-imidazole Drug Info [529625]
1-(1-Biphenyl-4-yl-2-phenyl-ethyl)-1H-imidazole Drug Info [529625]
1-(1-Biphenyl-4-yl-3-methyl-butyl)-1H-imidazole Drug Info [529625]
1-(1-Biphenyl-4-yl-butyl)-1H-imidazole Drug Info [529625]
1-(1-Biphenyl-4-yl-ethyl)-1H-imidazole Drug Info [529625]
1-(1-Biphenyl-4-yl-pentyl)-1H-imidazole Drug Info [529625]
1-(1-Biphenyl-4-yl-propyl)-1H-imidazole Drug Info [529625]
1-(3,4-dichlorobenzyl)-1H-imidazole Drug Info [528225]
1-(3,4-difluorobenzyl)-1H-imidazole Drug Info [528225]
1-(3,5-bis(trifluoromethyl)benzyl)-1H-imidazole Drug Info [528225]
1-(3,5-dibromobenzyl)-1H-imidazole Drug Info [528225]
1-(3,5-dichlorobenzyl)-1H-imidazole Drug Info [528225]
1-(3,5-difluorobenzyl)-1H-imidazole Drug Info [528225]
1-(3-(4-chlorophenyl)propyl)-1H-imidazole Drug Info [528335]
1-(3-(4-fluorophenyl)propyl)-1H-imidazole Drug Info [528335]
1-(3-phenylpropyl)-1H-imidazole Drug Info [528335]
1-(4-Bromobenzyl)-1H-imidazole Drug Info [528335]
1-(4-bromophenethyl)-1H-imidazole Drug Info [528335]
1-(4-chlorobenzyl)-1H-imidazole Drug Info [528335]
1-(4-chlorophenethyl)-1H-imidazole Drug Info [528335]
1-(4-fluorobenzyl)-1H-imidazole Drug Info [528335]
1-(4-iodobenzyl)-1H-imidazole Drug Info [531072]
1-(4-methyl-benzyl)-1H-imidazole Drug Info [528225]
1-(4-nitrobenzyl)-1H-imidazole Drug Info [528225]
1-(Bis-biphenyl-4-yl-methyl)-1H-imidazole Drug Info [529625]
1-Ethyl-5-(imidazol-1-yl-phenyl-methyl)-1H-indole Drug Info [525448]
1-Imidazol-1-ylmethyl-4-nitro-xanthen-9-one Drug Info [535139]
1-Imidazol-1-ylmethylxanthen-9-one Drug Info [551345]
2,3,4,5-Tetrafluoro-6-pentafluorophenylazo-phenol Drug Info [532449]
2,3,5,6-Tetrafluoro-4-pentafluorophenylazo-phenol Drug Info [532449]
2-(1-Imidazol-1-yl-ethyl)-9H-carbazole Drug Info [529625]
3-(1-Chloro-7-methoxy-naphthalen-2-yl)-pyridine Drug Info [527801]
3-(1-ethyl-3,4-dihydronaphthalen-2-yl)-pyridine Drug Info [528109]
3-(1-methyl-3,4-dihydronaphthalen-2-yl)-pyridine Drug Info [528109]
3-(6-Ethoxy-naphthalen-2-yl)-pyridine Drug Info [527801]
3-(6-methoxy-3,4-dihydronaphthalen-2-yl)pyridine Drug Info [528109]
3-(6-methoxynaphthalen-2-yl)pyridine Drug Info [529834]
3-fluoro-4'-(1-(pyridin-4-yl)propyl)biphenyl-4-ol Drug Info [530974]
3-Fluoro-4'-(pyridin-4-ylmethyl)biphenyl-4-ol Drug Info [531085]
3-[(4'-Hydroxybiphenyl-4-yl)methyl]pyridine Drug Info [531085]
3-[4-Fluoro-indan-(1Z)-ylidenemethyl]-pyridine Drug Info [527456]
4'-(1-(pyridin-4-yl)propyl)biphenyl-3-ol Drug Info [530974]
4'-(2-methyl-1-(pyridin-4-yl)propyl)biphenyl-3-ol Drug Info [530974]
4'-(Pyridin-4-ylmethyl)biphenyl-3,4-diamine Drug Info [531085]
4'-(Pyridin-4-ylmethyl)biphenyl-3,4-diol Drug Info [531085]
4'-(Pyridin-4-ylmethyl)biphenyl-3-amine Drug Info [531085]
4'-(Pyridin-4-ylmethyl)biphenyl-4-amine Drug Info [531085]
4'-(Pyridin-4-ylmethyl)biphenyl-4-carboxamide Drug Info [531085]
4-((1H-imidazol-1-yl)methyl)benzonitrile Drug Info [528225]
4-((1H-imidazol-1-yl)methyl)phenol Drug Info [531072]
4-((3',4'-Difluorobiphenyl-4-yl)methyl)pyridine Drug Info [531085]
4-(4'-Fluoro-biphenyl-4-ylmethyl)pyridine Drug Info [531085]
4-(4-(thiophen-2-yl)benzyl)pyridine Drug Info [531085]
4-(4-(thiophen-3-yl)benzyl)pyridine Drug Info [531085]
4-Bromo-1-imidazol-1-ylmethyl-xanthen-9-one Drug Info [535139]
4-Indan-(1Z)-ylidenemethyl-pyridine Drug Info [527456]
4-[(3'-Hydroxybiphenyl-4-yl)methyl]pyridine Drug Info [531085]
4-[(4'-Hydroxybiphenyl-4-yl)methyl]pyridine Drug Info [531085]
4-[1-(4'-Methoxybiphenyl-4-yl)propyl]pyridine Drug Info [531085]
4-[4-(6-methoxynaphthalen-2-yl)benzyl]pyridine Drug Info [531085]
4-[5-Bromo-indan-(1E)-ylidenemethyl]-pyridine Drug Info [527456]
4-[5-Bromo-indan-(1Z)-ylidenemethyl]-pyridine Drug Info [527456]
4-[5-Chloro-indan-(1E)-ylidenemethyl]-pyridine Drug Info [527456]
4-[5-Chloro-indan-(1Z)-ylidenemethyl]-pyridine Drug Info [527456]
4-[5-Fluoro-indan-(1E)-ylidenemethyl]-pyridine Drug Info [527456]
4-[5-Fluoro-indan-(1Z)-ylidenemethyl]-pyridine Drug Info [527456]
5-[4-(Pyridin-4-ylmethyl)phenyl]-1H-indole Drug Info [531085]
5-[5-Fluoro-indan-(1E)-ylidenemethyl]-pyrimidine Drug Info [527456]
6-(3-(pyridin-4-yl)phenyl)naphthalen-2-ol Drug Info [529160]
6-(pyridin-3-yl)-2-naphthonitrile Drug Info [529834]
6-Pyridin-3-yl-3,4-dihydroquinoline-2(1H)-thione Drug Info [529834]
6-Pyridin-3-yl-naphthalen-2-ol Drug Info [527801]
6-[4-(Pyridin-4-ylmethyl)phenyl]naphthalen-2-ol Drug Info [531085]
7-(1-(1H-imidazol-1-yl)ethyl)-9H-fluoren-2-ol Drug Info [529625]
ANG-3407 Drug Info [543411]
CFG920 Drug Info [532436]
ISOCONAZOLE Drug Info [526632]
N-(4'-Isonicotinoylbiphenyl-3-yl)acetamide Drug Info [531085]
N-3-(4-bromophenyl)propyl imidazole Drug Info [528335]
Rac-4'-(1-Imidazol-1-yl-propyl)-biphenyl-3,4-diol Drug Info [529960]
Rac-4'-(1-Imidazol-1-yl-propyl)-biphenyl-3,5-diol Drug Info [529960]
Rac-4'-(1-Imidazol-1-yl-propyl)-biphenyl-3-ol Drug Info [529960]
Rac-4'-(1-Imidazol-1-yl-propyl)-biphenyl-4-ol Drug Info [529960]
VN/107-1 Drug Info [543411]
Modulator ABIRATERONE Drug Info [527863], [531783]
Abiraterone acetate Drug Info
TAK-700 Drug Info [531762]
Target Expression Profile (TEP) and Drug Resistance Mutation (DRM)
TEP EXP Info
Pathways
BioCyc Pathway Superpathway of steroid hormone biosynthesis
Glucocorticoid biosynthesis
Androgen biosynthesis
KEGG Pathway Steroid hormone biosynthesis
Metabolic pathways
Ovarian steroidogenesis
Prolactin signaling pathway
PathWhiz Pathway Androgen and Estrogen Metabolism
Steroidogenesis
Reactome Androgen biosynthesis
Glucocorticoid biosynthesis
Endogenous sterols
WikiPathways Metapathway biotransformation
Steroid Biosynthesis
Oxidation by Cytochrome P450
Metabolism of steroid hormones and vitamin D
Glucocorticoid &amp
Mineralcorticoid Metabolism
Prostate Cancer
Phase 1 - Functionalization of compounds
References
Ref 527863Selective blockade of androgenic steroid synthesis by novel lyase inhibitors as a therapeutic strategy for treating metastatic prostate cancer. BJU Int. 2005 Dec;96(9):1241-6.
Ref 531762Orteronel (TAK-700), a novel non-steroidal 17,20-lyase inhibitor: effects on steroid synthesis in human and monkey adrenal cells and serum steroid levels in cynomolgus monkeys. J Steroid Biochem Mol Biol. 2012 Apr;129(3-5):115-28.
Ref 5317832011 FDA drug approvals. Nat Rev Drug Discov. 2012 Feb 1;11(2):91-4.
Ref 532436Recent progress in pharmaceutical therapies for castration-resistant prostate cancer. Int J Mol Sci. 2013 Jul 4;14(7):13958-78.
Ref 541843(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: 6745).
Ref 551871Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. 2015
Ref 525448Bioorg Med Chem Lett. 1999 Feb 8;9(3):333-6.New selective nonsteroidal aromatase inhibitors: synthesis and inhibitory activity of 2,3 or 5-(alpha-azolylbenzyl)-1H-indoles.
Ref 526632J Med Chem. 2003 Jun 5;46(12):2345-51.Three dimensional pharmacophore modeling of human CYP17 inhibitors. Potential agents for prostate cancer therapy.
Ref 527456J Med Chem. 2005 Mar 10;48(5):1563-75.Synthesis and evaluation of (pyridylmethylene)tetrahydronaphthalenes/-indanes and structurally modified derivatives: potent and selective inhibitors of aldosterone synthase.
Ref 527801J Med Chem. 2005 Oct 20;48(21):6632-42.Heteroaryl-substituted naphthalenes and structurally modified derivatives: selective inhibitors of CYP11B2 for the treatment of congestive heart failure and myocardial fibrosis.
Ref 527863Selective blockade of androgenic steroid synthesis by novel lyase inhibitors as a therapeutic strategy for treating metastatic prostate cancer. BJU Int. 2005 Dec;96(9):1241-6.
Ref 528109J Med Chem. 2006 Apr 6;49(7):2222-31.Synthesis and evaluation of heteroaryl-substituted dihydronaphthalenes and indenes: potent and selective inhibitors of aldosterone synthase (CYP11B2) for the treatment of congestive heart failure and myocardial fibrosis.
Ref 528225Bioorg Med Chem Lett. 2006 Aug 1;16(15):4011-5. Epub 2006 Jun 5.Synthesis and biochemical evaluation of a range of potent benzyl imidazole-based compounds as potential inhibitors of the enzyme complex 17alpha-hydroxylase/17,20-lyase (P450(17alpha)).
Ref 528335Bioorg Med Chem Lett. 2006 Sep 15;16(18):4752-6. Epub 2006 Jul 25.Synthesis, biochemical evaluation and rationalisation of the inhibitory activity of a range of 4-substituted phenyl alkyl imidazole-based inhibitors of the enzyme complex 17alpha-hydroxylase/17,20-lyase (P450(17alpha)).
Ref 529160Bioorg Med Chem Lett. 2008 Jan 1;18(1):267-73. Epub 2007 Oct 30.Synthesis, biological evaluation and molecular modelling studies of novel ACD- and ABD-ring steroidomimetics as inhibitors of CYP17.
Ref 529201Bioorg Med Chem. 2008 Feb 15;16(4):1992-2010. Epub 2007 Nov 4.Synthesis, biological evaluation and molecular modelling studies of methyleneimidazole substituted biaryls as inhibitors of human 17alpha-hydroxylase-17,20-lyase (CYP17). Part I: Heterocyclic modifications of the core structure.
Ref 529625Bioorg Med Chem. 2008 Aug 15;16(16):7715-27. Epub 2008 Jul 9.Synthesis, biological evaluation, and molecular modeling studies of methylene imidazole substituted biaryls as inhibitors of human 17alpha-hydroxylase-17,20-lyase (CYP17)--part II: Core rigidification and influence of substituents at the methylene bridge.
Ref 529834J Med Chem. 2008 Dec 25;51(24):8077-87.In vivo active aldosterone synthase inhibitors with improved selectivity: lead optimization providing a series of pyridine substituted 3,4-dihydro-1H-quinolin-2-one derivatives.
Ref 529960Eur J Med Chem. 2009 Jul;44(7):2765-75. Epub 2009 Jan 19.Novel CYP17 inhibitors: synthesis, biological evaluation, structure-activity relationships and modelling of methoxy- and hydroxy-substituted methyleneimidazolyl biphenyls.
Ref 530974J Med Chem. 2010 Jul 8;53(13):5049-53.Isopropylidene substitution increases activity and selectivity of biphenylmethylene 4-pyridine type CYP17 inhibitors.
Ref 531072Bioorg Med Chem Lett. 2010 Sep 1;20(17):5345-8. Epub 2010 Mar 3.Synthesis and biochemical evaluation of a range of (4-substituted phenyl)sulfonate derivatives of 4-hydroxybenzyl imidazole-based compounds as potent inhibitors of 17alpha-hydroxylase/17,20-lyase (P45017alpha) derived from rat testicular microsomes.
Ref 531085J Med Chem. 2010 Aug 12;53(15):5749-58.Replacement of imidazolyl by pyridyl in biphenylmethylenes results in selective CYP17 and dual CYP17/CYP11B1 inhibitors for the treatment of prostate cancer.
Ref 531762Orteronel (TAK-700), a novel non-steroidal 17,20-lyase inhibitor: effects on steroid synthesis in human and monkey adrenal cells and serum steroid levels in cynomolgus monkeys. J Steroid Biochem Mol Biol. 2012 Apr;129(3-5):115-28.
Ref 5317832011 FDA drug approvals. Nat Rev Drug Discov. 2012 Feb 1;11(2):91-4.
Ref 532436Recent progress in pharmaceutical therapies for castration-resistant prostate cancer. Int J Mol Sci. 2013 Jul 4;14(7):13958-78.
Ref 532449J Med Chem. 1990 Sep;33(9):2452-5.Hydroxyperfluoroazobenzenes: novel inhibitors of enzymes of androgen biosynthesis.
Ref 535139A new class of nonsteroidal aromatase inhibitors: design and synthesis of chromone and xanthone derivatives and inhibition of the P450 enzymes aromatase and 17 alpha-hydroxylase/C17,20-lyase. J Med Chem. 2001 Mar 1;44(5):672-80.
Ref 543411(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: 1361).
Ref 551345Novel highly potent and selective nonsteroidal aromatase inhibitors: synthesis, biological evaluation and structure-activity relationships investigation. J Med Chem. 2010 Jul 22;53(14):5347-51. doi: 10.1021/jm100319h.

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