Target Information

Target General Infomation
Target ID
T37848
Former ID
TTDS00418
Target Name
Cytochrome P450 3A4
Gene Name
CYP3A4
Synonyms
Albendazole monooxygenase; Albendazole sulfoxidase; CYP3A3; CYPIIIA3; CYPIIIA4; Cytochrome P450 3A3; HLp; NF-25; Nifedipine oxidase; P450-PCN1; Quinine 3-monooxygenase; Taurochenodeoxycholate 6-alpha-hydroxylase; CYP3A4
Target Type
Clinical Trial
Disease Cancer [ICD9: 140-229; ICD10: C00-C96]
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.
BioChemical Class
Oxidoreductases acting on paired donors
Target Validation
T37848
UniProt ID
P08684
EC Number
EC 1.14.13.97
Sequence
MALIPDLAMETWLLLAVSLVLLYLYGTHSHGLFKKLGIPGPTPLPFLGNILSYHKGFCMF
DMECHKKYGKVWGFYDGQQPVLAITDPDMIKTVLVKECYSVFTNRRPFGPVGFMKSAISI
AEDEEWKRLRSLLSPTFTSGKLKEMVPIIAQYGDVLVRNLRREAETGKPVTLKDVFGAYS
MDVITSTSFGVNIDSLNNPQDPFVENTKKLLRFDFLDPFFLSITVFPFLIPILEVLNICV
FPREVTNFLRKSVKRMKESRLEDTQKHRVDFLQLMIDSQNSKETESHKALSDLELVAQSI
IFIFAGYETTSSVLSFIMYELATHPDVQQKLQEEIDAVLPNKAPPTYDTVLQMEYLDMVV
NETLRLFPIAMRLERVCKKDVEINGMFIPKGVVVMIPSYALHRDPKYWTEPEKFLPERFS
KKNKDNIDPYIYTPFGSGPRNCIGMRFALMNMKLALIRVLQNFSFKPCKETQIPLKLSLG
GLLQPEKPVVLKVESRDGTVSGA
Drugs and Mode of Action
Drug(s) Curcumin Drug Info Phase 3 Cancer [1], [2]
Inhibitor (-)-clusin Drug Info [3]
(-)-cubebin Drug Info [3]
(-)-cubebinin Drug Info [3]
(-)-cubebininolide Drug Info [3]
(-)-dihydroclusin Drug Info [3]
(-)-thujaplicatintrimethyl ether Drug Info [3]
(-)-yatein Drug Info [3]
(5-pyridin-3-yl-furan-2-yl)methanethiol Drug Info [4]
(8R,8'R)-4-hydroxycubebinone Drug Info [3]
(8R,8'R,9'S)-5-methoxyclusin Drug Info [3]
1,1':4',1''-terphenyl-3,3''-diol Drug Info [5]
1,2-Diacetoxylycorine Drug Info [6]
1-(3,4-DICHLOROPHENYL)-6-(METHOXYMETHYL)-3-AZABICYCLO[4.1.0]HEPTANE (ENANTIOMERIC MIX) Drug Info [7]
1-(4-Butoxy-phenyl)-1H-imidazole Drug Info [8]
1-(METHOXYMETHYL)-6-(NAPHTHALEN-2-YL)-3-AZABICYCLO[4.1.0]HEPTANE (ENANTIOMERIC MIX) Drug Info [7]
1-Acetoxy-2-tert-butyldimethylsilyl-oxylycorine Drug Info [6]
1-Acetoxylycorine Drug Info [6]
1H-1,2,3-benzotriazol-1-amine Drug Info [9]
2,5-bis(4-hydroxybenzylidene)cyclopentanone Drug Info [10]
2-(2-(4-tert-Butylphenylthio)ethyl)-1H-imidazole Drug Info [11]
2-(4-Imidazol-1-yl-phenoxymethyl)-pyridine Drug Info [8]
2-Fluoro-4-[5-(3-hydroxyphenyl)-2-thienyl]phenol Drug Info [12]
2-fluoro-5-(3-methylthiophen-2-yl)pyridine Drug Info [4]
2-tert-Butyldimethylsilyloxylycorine Drug Info [6]
2-[3-(4-Imidazol-1-yl-phenoxy)-propyl]-pyridine Drug Info [8]
3,3-(1,3-Thiazole-2,5-diyl)diphenol Drug Info [5]
3-(3-methylthiophen-2-yl)pyridine Drug Info [4]
3-(5-((methylthio)methyl)furan-2-yl)pyridine Drug Info [4]
3-(5-[1,3]dithiolan-2-yl-furan-2-yl)pyridine Drug Info [4]
3-(pyridin-3-yl)prop-2-yn-1-amine Drug Info [4]
3-methoxy-5-(6-methoxynaphthalen-2-yl)pyridine Drug Info [13]
3-[3-(4-Imidazol-1-yl-phenoxy)-propyl]-pyridine Drug Info [8]
3-[3-(4-Methoxybenzyl)naphthalen-2-yl]pyridine Drug Info [14]
3-[5-(4-Hydroxyphenyl)-3-thienyl]phenol Drug Info [5]
4-(6-Methoxynaphthalen-2-yl)isoquinoline Drug Info [13]
4-[2-(4-Imidazol-1-yl-phenoxy)-ethyl]-morpholine Drug Info [8]
4-[3-(4-Imidazol-1-yl-phenoxy)-propyl]-pyridine Drug Info [8]
4-[5-(3-Hydroxyphenyl)-2-thienyl)-2-methyl]phenol Drug Info [12]
4-[5-(3-Hydroxyphenyl)-3-thienyl]-2-methylphenol Drug Info [12]
5-(2-phenethylpiperazin-1-yl)-1H-indazole Drug Info [15]
5-Pyridin-3-yl-thiophene-2-carbaldehyde oxime Drug Info [16]
6-(3,4-DICHLOROPHENYL)-1-[1-(METHYLOXY)-3-BUTEN-1-YL]-3-AZABICYCLO[4.1.0]HEPTANE (DIASTEREOMERIC MIX) Drug Info [7]
6-(3-Hydroxy-phenyl)-naphthalen-2-ol Drug Info [17]
6-Pyridin-3-yl-3,4-dihydronaphthalen-2(1H)-one Drug Info [18]
Ac-Phe-[Orn-Pro-cha-Trp-Arg] Drug Info [19]
Alpha-Hydroxy-Midazolam Drug Info [20]
Alpha-methylcubebin Drug Info [3]
BERGAPTOL Drug Info [21]
BMS-536924 Drug Info [22]
Curcumin Drug Info [10]
DIETHOXYFLOURESCEIN Drug Info [23]
DIHYDROCUBEBIN Drug Info [3]
ETHOXYCLUSIN Drug Info [3]
Geranylcoumarin Drug Info [21]
Go-Y026 Drug Info [10]
GSK-8062 Drug Info [24]
Heme Drug Info [25]
HINOKININ Drug Info [3]
JATRORRHIZINE Drug Info [26]
MEDIORESINOL Drug Info [3]
Methyl-(5-pyridin-3-yl-thiophen-2-yl)-amine Drug Info [16]
ML-3163 Drug Info [27]
ML-3375 Drug Info [27]
ML-3403 Drug Info [27]
PALMATINE Drug Info [26]
TILIROSIDE Drug Info [28]
Target Expression Profile (TEP) and Drug Resistance Mutation (DRM)
TEP EXP Info
Pathways
KEGG Pathway Steroid hormone biosynthesis
Linoleic acid metabolism
Retinol metabolism
Metabolism of xenobiotics by cytochrome P450
Drug metabolism - cytochrome P450
Drug metabolism - other enzymes
Metabolic pathways
Bile secretion
Chemical carcinogenesis
PathWhiz Pathway Caffeine Metabolism
Retinol Metabolism
Reactome Xenobiotics
Aflatoxin activation and detoxification
WikiPathways Metapathway biotransformation
Aflatoxin B1 metabolism
Estrogen metabolism
Benzo(a)pyrene metabolism
Tamoxifen metabolism
Tryptophan metabolism
Oxidation by Cytochrome P450
Nuclear Receptors in Lipid Metabolism and Toxicity
Nuclear Receptors Meta-Pathway
Farnesoid X Receptor Pathway
Vitamin D Receptor Pathway
Felbamate Metabolism
Lidocaine metabolism
Nifedipine Activity
Colchicine Metabolic Pathway
Irinotecan Pathway
Drug Induction of Bile Acid Pathway
Fatty Acid Omega Oxidation
Codeine and Morphine Metabolism
References
REF 1Nanocurcumin: a promising therapeutic advancement over native curcumin. Crit Rev Ther Drug Carrier Syst. 2013;30(4):331-68.
REF 2(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: 7000).
REF 3J Nat Prod. 2005 Jan;68(1):64-8.Potent CYP3A4 inhibitory constituents of Piper cubeba.
REF 4J Med Chem. 2006 Nov 30;49(24):6987-7001.Synthetic inhibitors of cytochrome P-450 2A6: inhibitory activity, difference spectra, mechanism of inhibition, and protein cocrystallization.
REF 5J Med Chem. 2008 Nov 13;51(21):6725-39. Epub 2008 Oct 15.Design, synthesis, biological evaluation and pharmacokinetics of bis(hydroxyphenyl) substituted azoles, thiophenes, benzenes, and aza-benzenes as potent and selective nonsteroidal inhibitors of 17beta-hydroxysteroid dehydrogenase type 1 (17beta-HSD1).
REF 6Bioorg Med Chem Lett. 2009 Jun 15;19(12):3233-7. Epub 2009 Apr 24.Selective cytochrome P450 3A4 inhibitory activity of Amaryllidaceae alkaloids.
REF 7J Med Chem. 2010 Jul 8;53(13):4989-5001.6-(3,4-dichlorophenyl)-1-[(methyloxy)methyl]-3-azabicyclo[4.1.0]heptane: a new potent and selective triple reuptake inhibitor.
REF 8Bioorg Med Chem Lett. 2004 Jan 19;14(2):333-6.Imidazole derivatives as new potent and selective 20-HETE synthase inhibitors.
REF 9Bioorg Med Chem Lett. 2001 Dec 3;11(23):2993-5.Discovery of a N'-hydroxyphenylformamidine derivative HET0016 as a potent and selective 20-HETE synthase inhibitor.
REF 10Eur J Med Chem. 2008 Aug;43(8):1621-31. Epub 2007 Nov 17.Structure-activity relationships for the inhibition of recombinant human cytochromes P450 by curcumin analogues.
REF 11J Med Chem. 2010 May 13;53(9):3840-4.Role of hydrophobic substituents on the terminal nitrogen of histamine in receptor binding and agonist activity: development of an orally active histamine type 3 receptor agonist and evaluation of its antistress activity in mice.
REF 12J Med Chem. 2009 Nov 12;52(21):6724-43.New insights into the SAR and binding modes of bis(hydroxyphenyl)thiophenes and -benzenes: influence of additional substituents on 17beta-hydroxysteroid dehydrogenase type 1 (17beta-HSD1) inhibitory activity and selectivity.
REF 13J Med Chem. 2008 Aug 28;51(16):5064-74. Epub 2008 Aug 1.Overcoming undesirable CYP1A2 inhibition of pyridylnaphthalene-type aldosterone synthase inhibitors: influence of heteroaryl derivatization onpotency and selectivity.
REF 14J Med Chem. 2008 Oct 9;51(19):6138-49. Epub 2008 Sep 3.Novel aldosterone synthase inhibitors with extended carbocyclic skeleton by a combined ligand-based and structure-based drug design approach.
REF 152-Substituted N-aryl piperazines as novel triple reuptake inhibitors for the treatment of depression, Bioorg. Med. Chem. Lett. 20(13):3941-3945 (2010).
REF 16J Med Chem. 2005 Jan 13;48(1):224-39.5-substituted, 6-substituted, and unsubstituted 3-heteroaromatic pyridine analogues of nicotine as selective inhibitors of cytochrome P-450 2A6.
REF 17J Med Chem. 2008 Apr 10;51(7):2158-69. Epub 2008 Mar 7.Design, synthesis, and biological evaluation of (hydroxyphenyl)naphthalene and -quinoline derivatives: potent and selective nonsteroidal inhibitors of 17beta-hydroxysteroid dehydrogenase type 1 (17beta-HSD1) for the treatment of estrogen-dependent diseases.
REF 18J 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 19Bioorg Med Chem Lett. 2006 Oct 1;16(19):5088-92. Epub 2006 Jul 28.Peptidomimetic C5a receptor antagonists with hydrophobic substitutions at the C-terminus: increased receptor specificity and in vivoactivity.
REF 20Bioorg Med Chem Lett. 2003 Nov 3;13(21):3643-5.Design and synthesis of a new fluorescent probe for cytochrome P450 3A4 (CYP 3A4).
REF 21Bioorg Med Chem. 2007 Jun 1;15(11):3684-91. Epub 2007 Mar 18.Radical scavenging and cytochrome P450 3A4 inhibitory activity of bergaptol and geranylcoumarin from grapefruit.
REF 22J Med Chem. 2008 Oct 9;51(19):5897-900. Epub 2008 Sep 3.Discovery and evaluation of 4-(2-(4-chloro-1H-pyrazol-1-yl)ethylamino)-3-(6-(1-(3-fluoropropyl)piperidin-4-yl)-4-methyl-1H-benzo[d]imidazol-2-yl)pyridin-2(1H)-one (BMS-695735), an orally efficacious inhibitor of insulin-like growth factor-1 receptor kinase with broad spectrum in vivo antitumor activity.
REF 23J Med Chem. 2010 Oct 14;53(19):7129-39.Exploration of the amine terminus in a novel series of 1,2,4-triazolo-3-yl-azabicyclo[3.1.0]hexanes as selective dopamine D3 receptor antagonists.
REF 24Bioorg Med Chem Lett. 2008 Aug 1;18(15):4339-43. Epub 2008 Jun 28.Conformationally constrained farnesoid X receptor (FXR) agonists: Naphthoic acid-based analogs of GW 4064.
REF 25The Protein Data Bank. Nucleic Acids Res. 2000 Jan 1;28(1):235-42.
REF 26J Nat Prod. 2007 Dec;70(12):1930-3. Epub 2007 Nov 10.Cytochrome P3A4 inhibitors and other constituents of Fibraurea tinctoria.
REF 27J Med Chem. 2003 Jul 17;46(15):3230-44.Novel substituted pyridinyl imidazoles as potent anticytokine agents with low activity against hepatic cytochrome P450 enzymes.
REF 28J Nat Prod. 2004 Nov;67(11):1839-41.Isolation of cytochrome P450 inhibitors from strawberry fruit, Fragaria ananassa.

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