Target Information

Target General Infomation
Target ID
T73726
Former ID
TTDS00359
Target Name
Fungal Cytochrome P450 51
Gene Name
ERG11
Synonyms
CYPL1; CYPLI; Cyt P450 14DM; Cytochrome P-450 lanosterol 14-alpha-demethylase; Cytochrome P450-dependent lanosterol 14-demethylase; Erg11p; LDM; Lanosterol 14 alpha-demethylase; Lanosterol 14-alpha demethylase; P450-14DM; P450L1; P450LI; Sterol 14-alpha demethylase; Sterol 14alpha-demethylase; ERG11
Target Type
Successful
Disease Aspergillosis [ICD10: B44]
Candidiasis infection [ICD9: 001-139, 112; ICD10: B37]
Chronic pain [ICD9: 338.2,780; ICD10: R52.1-R52.2, G89]
Dry eye disease [ICD9: 370.33; ICD10: H16.229]
Dermatological disease [ICD10: L00-L99]
Fungal infections [ICD9: 110-118; ICD10: B35-B49]
Hyperlipidaemia [ICD9: 272.0-272.4; ICD10: E78]
Invasive aspergillosis [ICD9: 117.3; ICD10: B44]
Onychomycosis [ICD10: B35.1]
Solid tumours [ICD9: 140-199, 210-229; ICD10: C00-D48]
Tinea pedis [ICD10: B35.6]
Tinea pedis; Tinea cruris; Tinea corporis; Cutaneous candidiasis; Tinea versicolor [ICD10: B353]
Function
Catalyzes C14-demethylation of lanosterol which is critical for ergosterol biosynthesis. It transforms lanosterol into 4,4'-dimethyl cholesta-8,14,24-triene-3-beta-ol.
BioChemical Class
Oxidoreductases acting on paired donors
Target Validation
T73726
UniProt ID
P10613
EC Number
EC 1.14.13.70
Sequence
MAIVETVIDGINYFLSLSVTQQISILLGVPFVYNLVWQYLYSLRKDRAPLVFYWIPWFGS
AASYGQQPYEFFESCRQKYGDVFSFMLLGKIMTVYLGPKGHEFVFNAKLSDVSAEDAYKH
LTTPVFGKGVIYDCPNSRLMEQKKFAKFALTTDSFKRYVPKIREEILNYFVTDESFKLKE
KTHGVANVMKTQPEITIFTASRSLFGDEMRRIFDRSFAQLYSDLDKGFTPINFVFPNLPL
PHYWRRDAAQKKISATYMKEIKSRRERGDIDPNRDLIDSLLIHSTYKDGVKMTDQEIANL
LIGILMGGQHTSASTSAWFLLHLGEKPHLQDVIYQEVVELLKEKGGDLNDLTYEDLQKLP
SVNNTIKETLRMHMPLHSIFRKVTNPLRIPETNYIVPKGHYVLVSPGYAHTSERYFDNPE
DFDPTRWDTAAAKANSVSFNSSDEVDYGFGKVSKGVSSPYLPFGGGRHRCIGEQFAYVQL
GTILTTFVYNLRWTIDGYKVPDPDYSSMVVLPTEPAEIIWEKRETCMF
Structure
4LXJ
Drugs and Mode of Action
Drug(s) Bifonazole Drug Info Approved Fungal infections [1]
Butoconazole Drug Info Approved Candidiasis infection [2], [3]
Econazole Drug Info Approved Tinea pedis; Tinea cruris; Tinea corporis; Cutaneous candidiasis; Tinea versicolor [3]
Efinaconazole Drug Info Approved Fungal infections [4]
Fluconazole Drug Info Approved Fungal infections [5]
Itraconazole Drug Info Approved Fungal infections [6]
Ketoconazole Drug Info Approved Fungal infections [7], [8]
Luliconazole Drug Info Approved Tinea pedis [9], [10], [3]
Miconazole Drug Info Approved Fungal infections [11], [12]
Oxiconazole Drug Info Approved Tinea pedis [13], [3]
Posaconazole Drug Info Approved Aspergillosis [14], [15], [16]
Sertaconazole Drug Info Approved Fungal infections [17]
Terconazole Drug Info Approved Candidiasis infection [18], [3]
Tioconazole Drug Info Approved Onychomycosis [19], [3]
Voriconazole Drug Info Approved Invasive aspergillosis [20]
CHLORIDE Drug Info Phase 3 Solid tumours [21], [22]
Econazole Drug Info Phase 3 Chronic pain [23]
Luliconazole 10% Drug Info Phase 2/3 Dry eye disease [24], [25]
E-1224 Drug Info Phase 2 Fungal infections [26]
EcoNail Drug Info Phase 2 Fungal infections [27]
Pramiconazole Drug Info Phase 2 Dermatological disease [28]
Embeconazole Drug Info Phase 1 Fungal infections [29]
Genaconazole Drug Info Phase 1 Fungal infections [30]
Abafungin Drug Info Discontinued in Phase 3 Fungal infections [31]
AZALANSTAT Drug Info Discontinued in Phase 2 Hyperlipidaemia [32]
Inhibitor Abafungin Drug Info [33]
ANALOGUE A Drug Info [34]
Bifonazole Drug Info [35], [36], [37]
Butoconazole Drug Info [38]
CP-320626 Drug Info [34]
E-1224 Drug Info [39]
EcoNail Drug Info [40]
Econazole Drug Info [41]
Efinaconazole Drug Info [4], [3]
Embeconazole Drug Info [42]
Ketoconazole Drug Info [43]
Luliconazole Drug Info [9], [3]
Oxiconazole Drug Info [44], [45]
Posaconazole Drug Info [46]
Sertaconazole Drug Info [47]
Terconazole Drug Info [48]
Tioconazole Drug Info [49]
Modulator AZALANSTAT Drug Info
CHLORIDE Drug Info [21]
Fluconazole Drug Info [50]
Genaconazole Drug Info [51]
Itraconazole Drug Info [50]
Luliconazole 10% Drug Info
Miconazole Drug Info [50]
Pramiconazole Drug Info [52]
Voriconazole Drug Info [50]
Binder FLC Drug Info [53]
References
REF 1Drug information of Bifonazole, 2008. eduDrugs.
REF 2FDA Approved Drug Products from FDA Official Website. 2009. Application Number: (NDA) 020421.
REF 3Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. 2015
REF 4Efinaconazole: Developmental and reproductive toxicity potential of a novel antifungal azole. Reprod Toxicol. 2015 Apr;52:18-25.
REF 5Fluconazole use as an important risk factor in the emergence of fluconazole-resistant Candida glabrata fungemia. Arch Intern Med. 2009 Aug 10;169(15):1444-5; author reply 1445.
REF 6FDA Approved Drug Products from FDA Official Website. 2009. Application Number: (ANDA) 076104.
REF 7FDA Approved Drug Products from FDA Official Website. 2009. Application Number: (ANDA) 075273.
REF 8(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: 2568).
REF 92013 FDA drug approvals. Nat Rev Drug Discov. 2014 Feb;13(2):85-9.
REF 10(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: 7366).
REF 11FDA Approved Drug Products from FDA Official Website. 2009. Application Number: (ANDA) 076773.
REF 12(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: 2449).
REF 13FDA Approved Drug Products from FDA Official Website. 2009. Application Number: (NDA) 019828.
REF 142006 drug approvals: finding the niche. Nat Rev Drug Discov. 2007 Feb;6(2):99-101.
REF 15Structural insights into inhibition of sterol 14alpha-demethylase in the human pathogen Trypanosoma cruzi. J Biol Chem. 2010 Aug 13;285(33):25582-90.
REF 16FDA Approved Drug Products from FDA Official Website. 2009. Application Number: (NDA) 022003.
REF 17FDA Approved Drug Products from FDA Official Website. 2009. Application Number: (NDA) 021385.
REF 18FDA Approved Drug Products from FDA Official Website. 2009. Application Number: (NDA) 021735.
REF 19FDA Approved Drug Products from FDA Official Website. 2009. Application Number: (ANDA) 075915.
REF 20Disk diffusion test and E-test with enriched Mueller-Hinton agar for determining susceptibility of Candida species to voriconazole and fluconazole. J Microbiol Immunol Infect. 2009 Apr;42(2):148-53.
REF 21Isavuconazonium: first global approval. Drugs. 2015 May;75(7):817-22.
REF 22(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: 2339).
REF 23Econazole nitrate foam 1% for the treatment of tinea pedis: results from two double-blind, vehicle-controlled, phase 3 clinical trials. J Drugs Dermatol. 2014 Jul;13(7):803-8.
REF 24ClinicalTrials.gov (NCT01431820) Safety and Efficacy of Luliconazole Solution, 10% in Subjects With Mild to Moderate Onychomycosis. U.S. National Institutes of Health.
REF 25Clinical pipeline report, company report or official report of Topica Pharmaceuticals.
REF 26ClinicalTrials.gov (NCT01489228) Proof-of-Concept Study of E1224 to Treat Adult Patients With Chagas Disease. U.S. National Institutes of Health.
REF 27ClinicalTrials.gov (NCT00385502) A Trial of the Safety and Efficacy of EcoNail in the Treatment of Fungus Infections of the Great Toenail. U.S. National Institutes of Health.
REF 28The efficacy of oral treatment with pramiconazole in pityriasis versicolor: a phase II a trial. Br J Dermatol. 2007 Jun;156(6):1385-8.
REF 29Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800014655)
REF 30In vivo efficacy of SM-8668 (Sch 39304), a new oral triazole antifungal agent. Antimicrob Agents Chemother. 1990 Jun;34(6):980-4.
REF 31Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800022887)
REF 32Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800002302)
REF 33Upregulation of sterol C14-demethylase expression in Trypanosoma cruzi treated with sterol biosynthesis inhibitors. Mol Biochem Parasitol. 2005 Nov;144(1):68-75.
REF 34Drug Metab Dispos. 2007 Mar;35(3):493-500. Epub 2006 Dec 28.Three-dimensional quantitative structure-activity relationship analysis of human CYP51 inhibitors.
REF 35Investigation of the role of cytochrome P450 2B4 active site residues in substrate metabolism based on crystal structures of the ligand-bound enzyme. Arch Biochem Biophys. 2006 Nov 1;455(1):61-7. Epub 2006 Sep 25.
REF 36Bifonazole and clotrimazole. Their mode of action and the possible reason for the fungicidal behaviour of bifonazole. Arzneimittelforschung. 1984;34(2):139-46.
REF 37Bifonazole, a biochemist's view. Dermatologica. 1984;169 Suppl 1:3-9.
REF 38Effects of terconazole and other azole antifungal agents on the sterol and carbohydrate composition of Candida albicans. Diagn Microbiol Infect Dis. 1990 Jan-Feb;13(1):31-5.
REF 39Recent Developments in Sterol 14-demethylase Inhibitors for Chagas Disease. Int J Parasitol Drugs Drug Resist. 2012 Dec;2:236-242.
REF 40Azole binding properties of Candida albicans sterol 14-alpha demethylase (CaCYP51). Antimicrob Agents Chemother. 2010 Oct;54(10):4235-45.
REF 41Differential azole antifungal efficacies contrasted using a Saccharomyces cerevisiae strain humanized for sterol 14 alpha-demethylase at the homologous locus. Antimicrob Agents Chemother. 2008 Oct;52(10):3597-603. Epub 2008 Aug 11.
REF 42CS-758. Antifungal lanosterol 14alpha-demethylase inhibitor, 003, vol28, no3, 217-223.
REF 43Clinical pharmacokinetics and pharmacodynamics of solifenacin. Clin Pharmacokinet. 2009;48(5):281-302. doi: 10.2165/00003088-200948050-00001.
REF 44Antifungal agents: mechanisms of action. Trends Microbiol. 2003 Jun;11(6):272-9.
REF 45Antifungal agents: mode of action in yeast cells. Rev Esp Quimioter. 2006 Jun;19(2):130-9.
REF 46A new, broad-spectrum azole antifungal: posaconazole--mechanisms of action and resistance, spectrum of activity. Mycoses. 2006;49 Suppl 1:2-6.
REF 47Sertaconazole: a review of its use in the management of superficial mycoses in dermatology and gynaecology. Drugs. 2009;69(3):339-59. doi: 10.2165/00003495-200969030-00009.
REF 48Mode of action of anti-Candida drugs: focus on terconazole and other ergosterol biosynthesis inhibitors. Am J Obstet Gynecol. 1991 Oct;165(4 Pt 2):1193-9.
REF 49Biological spectra analysis: Linking biological activity profiles to molecular structure. Proc Natl Acad Sci U S A. 2005 Jan 11;102(2):261-6. Epub 2004 Dec 29.
REF 50Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services.
REF 51New targets and delivery systems for antifungal therapy. Med Mycol. 2000;38 Suppl 1:335-47.
REF 52Interpreting expression profiles of cancers by genome-wide survey of breadth of expression in normal tissues. Genomics 2005 Aug;86(2):127-41.
REF 53Chemosensitization of fluconazole resistance in Saccharomyces cerevisiae and pathogenic fungi by a D-octapeptide derivative. Antimicrob Agents Chemother. 2004 Apr;48(4):1256-71.

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