Target Information

Target General Infomation
Target ID
T97035
Former ID
TTDS00373
Target Name
Tyrosine oxidase
Gene Name
TYR
Synonyms
LB24-AB; Monophenol monooxygenase; SK29-AB; Tumor rejection antigen AB; Tyrosinase; TYR
Target Type
Successful
Disease Melanoma [ICD9: 172; ICD10: C43]
Melasma [ICD10: L81.1]
Rheumatoid arthritis [ICD9: 710-719, 714; ICD10: M05-M06]
Vitiligo [ICD9: 709.01; ICD10: L80]
Function
This is a copper-containing oxidase that functions in the formation of pigments such as melanins and other polyphenolic compounds. Catalyzes the rate-limiting conversions of tyrosine to DOPA, DOPA to DOPA-quinoneand possibly 5,6-dihydroxyindole to indole-5,6 quinone.
BioChemical Class
Tyrosinase
Target Validation
T97035
UniProt ID
P14679
EC Number
EC 1.14.18.1
Sequence
MLLAVLYCLLWSFQTSAGHFPRACVSSKNLMEKECCPPWSGDRSPCGQLSGRGSCQNILL
SNAPLGPQFPFTGVDDRESWPSVFYNRTCQCSGNFMGFNCGNCKFGFWGPNCTERRLLVR
RNIFDLSAPEKDKFFAYLTLAKHTISSDYVIPIGTYGQMKNGSTPMFNDINIYDLFVWMH
YYVSMDALLGGSEIWRDIDFAHEAPAFLPWHRLFLLRWEQEIQKLTGDENFTIPYWDWRD
AEKCDICTDEYMGGQHPTNPNLLSPASFFSSWQIVCSRLEEYNSHQSLCNGTPEGPLRRN
PGNHDKSRTPRLPSSADVEFCLSLTQYESGSMDKAANFSFRNTLEGFASPLTGIADASQS
SMHNALHIYMNGTMSQVQGSANDPIFLLHHAFVDSIFEQWLRRHRPLQEVYPEANAPIGH
NRESYMVPFIPLYRNGDFFISSKDLGYDYSYLQDSDPDSFQDYIKSYLEQASRIWSWLLG
AAMVGAVLTALLAGLVSLLCRHKRKQLPEEKQPLLMEKEDYHSLYQSHL
Drugs and Mode of Action
Drug(s) Hydroquinone Drug Info Approved Melasma [1]
Monobenzone Drug Info Approved Vitiligo [2], [3]
Melanoma vaccine Drug Info Phase 3 Melanoma [4]
Multi-epitope peptide melanoma vaccine Drug Info Phase 3 Melanoma [4]
MKC-1106-MT Drug Info Phase 2 Melanoma [5]
Multi-epitope tyrosinase/gp100 vaccine Drug Info Phase 2 Melanoma [6]
Polynoma-1 Drug Info Phase 2 Melanoma [7]
DNA vaccine Drug Info Phase 1 Melanoma [8]
Inhibitor (+/-)-Daedalin A Drug Info [9]
1'-(4-Methyl-benzyl)-[1,4']bipiperidinyl Drug Info [10]
1-(1,4-diacetylphenyl)dithiosemicarbazide Drug Info [11]
1-(1-(4-bromophenyl)ethylidene)thiosemicarbazide Drug Info [11]
1-(1-(4-fluorophenyl)ethylidene)thiosemicarbazide Drug Info [11]
1-(1-(pyrazin-2-yl)ethylidene)thiosemicarbazide Drug Info [11]
1-(1-(pyridin-3-yl)ethylidene)thiosemicarbazide Drug Info [11]
1-(1-(thiophen-2-yl)ethylidene)thiosemicarbazide Drug Info [11]
1-(1-p-tolylethylidene)thiosemicarbazide Drug Info [11]
1-(1-phenylethylidene)thiosemicarbazide Drug Info [11]
1-(2,5-Dimethyl-1H-pyrrol-1-yl)thiourea Drug Info [12]
1-(3-Methylbutylidene)thiosemicarbazide Drug Info [12]
1-(3-Oxocyclohexylidene)thiosemicarbazide Drug Info [12]
1-(3-phenoxypropyl)-4-(piperidin-1-yl)piperidine Drug Info [10]
1-(3-Phenylallylidene)thiosemicarbazide Drug Info [12]
1-(4-(benzyloxy)phenyl)-3-hydroxyurea Drug Info [13]
1-(4-bromophenyl)-3-hydroxyurea Drug Info [13]
1-(4-Methylpent-3-en-2-ylidene)thiosemicarbazide Drug Info [12]
1-(But-2-enylidene)thiosemicarbazide Drug Info [12]
1-(Butan-2-ylidene)thiosemicarbazide Drug Info [12]
1-(Propan-2-ylidene)thiosemicarbazide Drug Info [12]
1-Cyclohexylidenethiosemicarbazide Drug Info [12]
1-Cyclopentylidenethiosemicarbazide Drug Info [12]
1-Ethylidenethiosemicarbazide Drug Info [12]
1-hydroxy-3-(4-(trifluoromethyl)phenyl)urea Drug Info [13]
1-hydroxy-3-(4-nitrophenyl)urea Drug Info [13]
1-hydroxy-3-phenylurea Drug Info [13]
1-Propylidenethiosemicarbazide Drug Info [12]
2,2',4,4',6'-pentahydroxychalcone Drug Info [14]
2,2',4,4'-tetrahydroxy-6'-methoxychalcone Drug Info [14]
2,2',4,4'-tetrahydroxychalcone Drug Info [14]
2,2'-bi(1,3,4-thiadiazole)-5,5'(4H,4'H)-dithione Drug Info [15]
2,4,3',5'-tetrahydroxybibenzyl Drug Info [16]
2-(butylthiomethyl)-5-hydroxy-4H-pyran-4-one Drug Info [17]
2-(cyclohexylthiomethyl)-5-hydroxy-4H-pyran-4-one Drug Info [17]
2-(ethylthiomethyl)-5-hydroxy-4H-pyran-4-one Drug Info [17]
2-(heptylthiomethyl)-5-hydroxy-4H-pyran-4-one Drug Info [17]
2-(hexylthiomethyl)-5-hydroxy-4H-pyran-4-one Drug Info [17]
2-hydroxy-3-isopropyl-2,4,6-cycloheptatrien-1-one Drug Info [18]
2-hydroxy-5-isopropyl-2,4,6-cycloheptatrien-1-one Drug Info [18]
2-hydroxyphenethyl 3,4,5-trihydroxybenzoate Drug Info [19]
3,4-dihydroxybenzaldehyde-O-ethyloxime Drug Info [20]
3-(2,4-dihydroxyphenyl)propionic acid Drug Info [21]
3-hydroxyphenethyl 3,4,5-trihydroxybenzoate Drug Info [19]
3hydroxy-1-methyl-1-phenylurea Drug Info [13]
4',4-Dihydroxychalcone Drug Info [22]
4'-(4-Aminobenzensulfonamide)-4-hydroxychalcone Drug Info [22]
4'-(4-Fluorobenzensulfonamide)-4-hydroxychalcone Drug Info [22]
4'-(4-Nitrobenzensulfonamide)-4-hydroxychalcone Drug Info [22]
4'-(Benzensulfonamide)-4-hydroxychalcone Drug Info [22]
4'-(p-Toluenesulfonamide)-4-hydroxychalcone Drug Info [22]
4'-Amino-4-hydroxychalcone Drug Info [22]
4,4'-(ethane-1,2-diyl)dibenzene-1,3-diol Drug Info [23]
4-(6-hydroxynaphthalen-2-yl)benzene-1,3-diol Drug Info [24]
4-adamantyl resorcinol Drug Info [25]
4-hexyl resorcinol Drug Info [26]
4-hydroxyphenethyl 3,4,5-trihydroxybenzoate Drug Info [19]
5,5'-methylenebis(1,3,4-oxadiazole-2(3H)-thione) Drug Info [15]
5,5'-methylenebis(1,3,4-thiadiazole-2(3H)-thione) Drug Info [15]
5-(3-hydroxyphenyl)-1,3,4-oxadiazole-2(3H)-thione Drug Info [15]
5-(4-hydroxyphenyl)-1,3,4-oxadiazole-2(3H)-thione Drug Info [15]
5-(6-hydroxy-2-naphthyl)-1,2,3-benzenetriol Drug Info [27]
5-(6-hydroxynaphthalen-2-yl)benzene-1,3-diol Drug Info [24]
5-(pyridin-4-yl)-1,3,4-oxadiazole-2(3H)-thione Drug Info [15]
5-(pyridin-4-yl)-1,3,4-thiadiazole-2(3H)-thione Drug Info [15]
5-benzhydryl-1,3,4-oxadiazole-2(3H)-thione Drug Info [15]
5-benzhydryl-1,3,4-thiadiazole-2(3H)-thione Drug Info [15]
5-benzyl-1,3,4-oxadiazole-2(3H)-thione Drug Info [15]
5-cyclohexyl-1,3,4-oxadiazole-2(3H)-thione Drug Info [15]
5-hydroxy-2-(pentylthiomethyl)-4H-pyran-4-one Drug Info [17]
5-hydroxy-2-(propylthiomethyl)-4H-pyran-4-one Drug Info [17]
5-phenyl-1,3,4-oxadiazole-2(3H)-thione Drug Info [15]
5-phenyl-1,3,4-thiadiazole-2(3H)-thione Drug Info [15]
5-{8(Z),-pentadecenyl}resorcinol Drug Info [28]
5-{8(Z),11(Z),14-pentadecatrienyl}resorcinol Drug Info [28]
5-{8(Z),11(Z)-pentadecadienyl}resorcinol Drug Info [28]
6-(3-Hydroxy-phenyl)-naphthalen-2-ol Drug Info [24]
7,3',4'-trihydroxyisoflavone Drug Info [29]
7,8,4'-trihydroxyisoflavone Drug Info [29]
7-(3,5-dihydroxyphenyl)naphthalene-1,3-diol Drug Info [24]
ASKENDOSIDE B Drug Info [30]
Broussonin C Drug Info [31]
Crocusatin-K Drug Info [32]
DAEDALIN A Drug Info [9]
ETHISTERONE Drug Info [33]
HINOKITIOL Drug Info [18]
Hydroquinone Drug Info [34]
Kazinol C Drug Info [31]
Kazinol F Drug Info [31]
KAZINOL S Drug Info [31]
KOJIC ACID Drug Info [35]
Kojic acid-phenylalanine amide Drug Info [36]
Monobenzone Drug Info [34]
N-(2,4-dihydroxybenzyl)-3,4,5-trihydroxybenzamide Drug Info [37]
N-(2,4-dihydroxybenzyl)-3,4-dihydroxybenzamide Drug Info [37]
N-(2,4-dihydroxybenzyl)-3,5-dihydroxybenzamide Drug Info [37]
N-butylresorcinol Drug Info [25]
OXYRESVERATROL Drug Info [16]
PHENYLTHIOUREA Drug Info [13]
ROSMARINIC ACID Drug Info [35]
S-2-(o-toluidino)-2-oxoethyl carbamothioate Drug Info [38]
SODIUM ZINC DIHYDROLIPOYLHISTIDINATE Drug Info [39]
SRI-224 Drug Info [20]
TROPOLONE Drug Info [20]
Modulator MKC-1106-MT Drug Info [40]
Target Expression Profile (TEP) and Drug Resistance Mutation (DRM)
TEP EXP Info
Pathways
BioCyc Pathway (S)-reticuline biosynthesis
Eumelanin biosynthesis
L-dopachrome biosynthesis
KEGG Pathway Tyrosine metabolism
Riboflavin metabolism
Metabolic pathways
Melanogenesis
PathWhiz Pathway Riboflavin Metabolism
Tyrosine Metabolism
WikiPathways Dopamine metabolism
References
REF 1Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. 2015
REF 2FDA Approved Drug Products from FDA Official Website. 2009. Application Number: (NDA) 008173.
REF 3(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: 6830).
REF 4ClinicalTrials.gov (NCT00036816) Vaccine Therapy in Treating Patients With Melanoma of the Eye. U.S. National Institutes of Health.
REF 5ClinicalTrials.gov (NCT01026051) Safety, Immune and Tumor Response to a Multi-component Immune Based Therapy (MKC1106-MT) for Patients With Melanoma. U.S. National Institutes of Health.
REF 6ClinicalTrials.gov (NCT00003362) Vaccine Therapy Plus Immune Adjuvants in Treating Patients With Advanced Melanoma. U.S. National Institutes of Health.
REF 7An immuno-oncology company developing a novel polyvalent antigen therapy for the treatment of melanoma. Polynoma. 2015.
REF 8Safety and immunogenicity of tyrosinase DNA vaccines in patients with melanoma. Mol Ther. 2007 Nov;15(11):2044-50. Epub 2007 Aug 28.
REF 9Bioorg Med Chem Lett. 2010 Feb 1;20(3):1063-4. Epub 2009 Dec 11.Asymmetric syntheses of daedalin A and quercinol and their tyrosinase inhibitory activity.
REF 10Eur J Med Chem. 2007 Nov-Dec;42(11-12):1370-81. Epub 2007 Feb 23.Dragon method for finding novel tyrosinase inhibitors: Biosilico identification and experimental in vitro assays.
REF 11Bioorg Med Chem. 2008 Feb 1;16(3):1096-102.1-(1-Arylethylidene)thiosemicarbazide derivatives: a new class of tyrosinase inhibitors.
REF 12Eur J Med Chem. 2009 Apr;44(4):1773-8. Epub 2008 Apr 27.A class of potent tyrosinase inhibitors: alkylidenethiosemicarbazide compounds.
REF 13Bioorg Med Chem Lett. 2008 Jun 15;18(12):3607-10. Epub 2008 May 4.Analogues of N-hydroxy-N'-phenylthiourea and N-hydroxy-N'-phenylurea as inhibitors of tyrosinase and melanin formation.
REF 14Bioorg Med Chem. 2007 Mar 15;15(6):2396-402. Epub 2007 Jan 17.Synthesis and evaluation of 2',4',6'-trihydroxychalcones as a new class of tyrosinase inhibitors.
REF 15Bioorg Med Chem. 2010 Jun 1;18(11):4042-8. Epub 2010 Apr 13.New potent inhibitors of tyrosinase: novel clues to binding of 1,3,4-thiadiazole-2(3H)-thiones, 1,3,4-oxadiazole-2(3H)-thiones, 4-amino-1,2,4-triazole-5(4H)-thiones, and substituted hydrazides to the dicopper active site.
REF 16Bioorg Med Chem Lett. 2006 Nov 1;16(21):5650-3. Epub 2006 Aug 17.Chemical transformations of oxyresveratrol (trans-2,4,3',5'-tetrahydroxystilbene) into a potent tyrosinase inhibitor and a strong cytotoxic agent.
REF 17Bioorg Med Chem Lett. 2010 Nov 15;20(22):6569-71. Epub 2010 Sep 21.Kojyl thioether derivatives having both tyrosinase inhibitory and anti-inflammatory properties.
REF 18Bioorg Med Chem. 2010 Nov 15;18(22):8112-8. Epub 2010 Oct 12.Structural insights into the hot spot amino acid residues of mushroom tyrosinase for the bindings of thujaplicins.
REF 19Bioorg Med Chem Lett. 2007 Oct 1;17(19):5462-4. Epub 2007 Jul 25.Synthetic tyrosyl gallate derivatives as potent melanin formation inhibitors.
REF 20Bioorg Med Chem Lett. 2009 Nov 1;19(21):6157-60. Epub 2009 Sep 10.Discovery of 4-functionalized phenyl-O-beta-D-glycosides as a new class of mushroom tyrosinase inhibitors.
REF 21J Med Chem. 2007 May 31;50(11):2676-81. Epub 2007 Apr 21.Enhanced substituted resorcinol hydrophobicity augments tyrosinase inhibition potency.
REF 22Eur J Med Chem. 2010 May;45(5):2010-7. Epub 2010 Jan 28.Evaluation of anti-pigmentary effect of synthetic sulfonylamino chalcone.
REF 23Bioorg Med Chem Lett. 2008 Oct 1;18(19):5252-4. Epub 2008 Aug 22.Molecular design of potent tyrosinase inhibitors having the bibenzyl skeleton.
REF 24Bioorg Med Chem Lett. 2007 Jan 15;17(2):461-4. Epub 2006 Oct 12.Syntheses of hydroxy substituted 2-phenyl-naphthalenes as inhibitors of tyrosinase.
REF 25Bioorg Med Chem Lett. 2009 Mar 1;19(5):1532-3. Epub 2009 Jan 1.Studies on depigmenting activities of dihydroxyl benzamide derivatives containing adamantane moiety.
REF 26Bioorg Med Chem Lett. 2009 Jan 1;19(1):36-9. Epub 2008 Nov 13.PEG-immobilization of cardol and soluble polymer-supported synthesis of some cardol-coumarin derivatives: preliminary evaluation of their inhibitory activity on mushroom tyrosinase.
REF 27Bioorg Med Chem Lett. 2010 Aug 15;20(16):4882-4. Epub 2010 Jun 19.A newly synthesized, potent tyrosinase inhibitor: 5-(6-hydroxy-2-naphthyl)-1,2,3-benzenetriol.
REF 28Tyrosinase inhibitors from Anacardium occidentale fruits. J Nat Prod. 1994 Apr;57(4):545-51.
REF 29Bioorg Med Chem Lett. 2010 Feb 1;20(3):1162-4. Epub 2009 Dec 6.Natural ortho-dihydroxyisoflavone derivatives from aged Korean fermented soybean paste as potent tyrosinase and melanin formation inhibitors.
REF 30Bioorg Med Chem Lett. 2006 Jan 15;16(2):324-30. Epub 2005 Nov 3.New tyrosinase inhibitors selected by atomic linear indices-based classification models.
REF 31Bioorg Med Chem. 2009 Jan 1;17(1):35-41. Epub 2008 Nov 18.Tyrosinase inhibitory effects of 1,3-diphenylpropanes from Broussonetia kazinoki.
REF 32J Nat Prod. 2004 Mar;67(3):437-40.Antityrosinase principles and constituents of the petals of Crocus sativus.
REF 33Bioorg Med Chem. 2007 Feb 1;15(3):1483-503. Epub 2006 Nov 2.TOMOCOMD-CARDD descriptors-based virtual screening of tyrosinase inhibitors: evaluation of different classification model combinations using bond-based linear indices.
REF 34Identification of an Alkylhydroquinone from Rhus succedanea as an Inhibitor of Tyrosinase and Melanogenesis. J Agric Food Chem. 2009 Mar 25;57(6):2200-5.
REF 35Bioorg Med Chem Lett. 2010 Dec 15;20(24):7393-6. Epub 2010 Oct 14.A novel ring-expanded product with enhanced tyrosinase inhibitory activity from classical Fe-catalyzed oxidation of rosmarinic acid,a potent antioxidative Lamiaceae polyphenol.
REF 36Bioorg Med Chem Lett. 2009 Oct 1;19(19):5586-9. Epub 2009 Aug 14.Kojic acid-amino acid conjugates as tyrosinase inhibitors.
REF 37Bioorg Med Chem Lett. 2006 May 15;16(10):2682-4. Epub 2006 Mar 2.N-Benzylbenzamides: a new class of potent tyrosinase inhibitors.
REF 38Bioorg Med Chem Lett. 2007 Dec 15;17(24):6871-5. Epub 2007 Oct 12.Discovery of small-molecule inhibitors of tyrosinase.
REF 39Bioorg Med Chem. 2007 Mar 1;15(5):1967-75. Epub 2006 Dec 31.Modulating effects of a novel skin-lightening agent, alpha-lipoic acid derivative, on melanin production by the formation of DOPA conjugate products.
REF 40Interpreting expression profiles of cancers by genome-wide survey of breadth of expression in normal tissues. Genomics 2005 Aug;86(2):127-41.

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