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Temsirolimus

July 24, 2017
Common Name

Temsirolimus Description

Temsirolimus is an intravenous drug for the treatment of renal cell carcinoma (RCC), developed by Wyeth Pharmaceuticals and approved by the FDA in late May 2007, and was also approved by the European Medicines Agency (EMEA) on November 2007. It is a derivative of sirolimus and is sold as Torisel. Structure

MOLSDFPDBSMILESInChI

Synonyms

Value Source CCI 779Kegg 42-[3-Hydroxy-2-(hydroxymethyl)-2-methylpropanoate]rapamycinKegg ToriselKegg 42-[3-Hydroxy-2-(hydroxymethyl)-2-methylpropanoic acid]rapamycinGenerator CCI-779HMDB Wyeth brand OF temsirolimusMeSH

Chemical Formlia

C56H87NO16 Average Molecliar Weight

1030.2871 Monoisotopic Molecliar Weight

1029.602485741 IUPAC Name

(1R,2R,4S)-4-[(2R)-2-[(1R,9S,12S,15R,16E,18R,19R,21R,23S,24E,26E,28E,30S,32S,35R)-1,18-dihydroxy-19,30-dimethoxy-15,17,21,23,29,35-hexamethyl-2,3,10,14,20-pentaoxo-11,36-dioxa-4-azatricyclo[30.3.1.0⁴,⁹]hexatriaconta-16,24,26,28-tetraen-12-yl]propyl]-2-methoxycyclohexyl 3-hydroxy-2-(hydroxymethyl)-2-methylpropanoate Traditional Name

temsirolimus CAS Registry Number

162635-04-3 SMILES

OCC(C)(CO)C(=O)O[C@@H]1CC[C@@H](C[C@@H](C)[C@]2([H])CC(=O)[C@H](C)C=C(C)[C@@H](O)[C@@H](OC)C(=O)[C@H](C)C[C@H](C)C=CC=CC=C(C)[C@@H](OC)C[C@]3([H])CC[C@@H](C)[C@@](O)(O3)C(=O)C(=O)N3CCCC[C@H]3C(=O)O2)C[C@H]1OC

InChI Identifier

InChI=1S/C56H87NO16/c1-33-17-13-12-14-18-34(2)45(68-9)29-41-22-20-39(7)56(67,73-41)51(63)52(64)57-24-16-15-19-42(57)53(65)71-46(30-43(60)35(3)26-38(6)49(62)50(70-11)48(61)37(5)25-33)36(4)27-40-21-23-44(47(28-40)69-10)72-54(66)55(8,31-58)32-59/h12-14,17-18,26,33,35-37,39-42,44-47,49-50,58-59,62,67H,15-16,19-25,27-32H2,1-11H3/b14-12+,17-13+,34-18+,38-26+/t33-,35-,36-,37-,39-,40+,41+,42+,44-,45+,46+,47-,49-,50+,56-/m1/s1

InChI Key

CBPNZQVSJQDFBE-FUXHJELOSA-N Chemical Taxonomy Description

This compound belongs to the class of organic compounds known as macrolide lactams. These are cyclic polyketides containing both a cyclic amide and a cyclic ester group. Kingdom

Organic compounds Super Class

Phenylpropanoids and polyketides Class

Macrolide lactams Sub Class

Not Available Direct Parent

Macrolide lactams Alternative Parents

  • Alpha amino acid esters
  • Macrolides and analogues
  • Beta hydroxy acids and derivatives
  • Piperidines
  • Oxanes
  • Dicarboxylic acids and derivatives
  • Tertiary carboxylic acid amides
  • Secondary alcohols
  • Carboxylic acid esters
  • Cyclic ketones
  • Lactones
  • Lactams
  • Hemiacetals
  • Azacyclic compounds
  • Oxacyclic compounds
  • Dialkyl ethers
  • Organonitrogen compounds
  • Organopnictogen compounds
  • Primary alcohols
  • Organic oxides
  • Hydrocarbon derivatives

    • Substituents

  • Macrolide lactam
  • Alpha-amino acid ester
  • Macrolide
  • Alpha-amino acid or derivatives
  • Beta-hydroxy acid
  • Dicarboxylic acid or derivatives
  • Hydroxy acid
  • Oxane
  • Piperidine
  • Tertiary carboxylic acid amide
  • Carboxamide group
  • Carboxylic acid ester
  • Hemiacetal
  • Ketone
  • Lactam
  • Lactone
  • Cyclic ketone
  • Secondary alcohol
  • Carboxylic acid derivative
  • Organoheterocyclic compound
  • Azacycle
  • Oxacycle
  • Dialkyl ether
  • Ether
  • Carbonyl group
  • Organic oxide
  • Organic nitrogen compound
  • Hydrocarbon derivative
  • Organic oxygen compound
  • Organonitrogen compound
  • Organooxygen compound
  • Organopnictogen compound
  • Alcohol
  • Primary alcohol
  • Aliphatic heteropolycyclic compound

    • Molecliar Framework

    Aliphatic heteropolycyclic compounds External Descriptors

  • lactam (CHEBI:79699 )
  • macrolide (CHEBI:79699 )

    • Ontology Status

    Expected but not Quantified Origin

  • Drug

    • Biofunction

  • Antineoplastic Agents
  • Protein Kinase Inhibitors

    • Application

  • Pharmaceutical

    • Cellliar locations

  • Membrane

    • Physical Properties State

    Solid Experimental Properties

    Property Value Reference Melting PointNot AvailableNot Available Boiling PointNot AvailableNot Available Water Solubility2.35e-03 g/LNot Available LogPNot AvailableNot Available

    Predicted Properties

    Property Value Source Water Solubility0.0024 mg/mLALOGPS logP4.39ALOGPS logP7.13ChemAxon logS-5.6ALOGPS pKa (Strongest Acidic)9.96ChemAxon pKa (Strongest Basic)-2.9ChemAxon Physiological Charge0ChemAxon Hydrogen Acceptor Count14ChemAxon Hydrogen Donor Count4ChemAxon Polar Surface Area241.96 Å2ChemAxon Rotatable Bond Count11ChemAxon Refractivity277.07 m3·mol-1ChemAxon Polarizability112.71 Å3ChemAxon Number of Rings4ChemAxon Bioavailability0ChemAxon Rlie of FiveYesChemAxon Ghose FilterYesChemAxon Vebers RlieYesChemAxon MDDR-like RlieYesChemAxon

    Spectra Spectra

    Spectrum Type Description Splash Key Predicted LC-MS/MS

    Predicted LC-MS/MS Spectrum – 10V, PositiveNot Available Predicted LC-MS/MS

    Predicted LC-MS/MS Spectrum – 20V, PositiveNot Available Predicted LC-MS/MS

    Predicted LC-MS/MS Spectrum – 40V, PositiveNot Available Predicted LC-MS/MS

    Predicted LC-MS/MS Spectrum – 10V, NegativeNot Available Predicted LC-MS/MS

    Predicted LC-MS/MS Spectrum – 20V, NegativeNot Available Predicted LC-MS/MS

    Predicted LC-MS/MS Spectrum – 40V, NegativeNot Available

    Biological Properties Cellliar Locations

  • Membrane

    • Biofluid Locations

  • Blood
  • Urine

    • Tissue Location

    Not Available Pathways

    Not Available Normal Concentrations

    Biofluid Status Value Age Sex Condition Reference Details BloodExpected but not Quantified Not AvailableNot AvailableTaking drug identified by DrugBank entry DB06287

  • 21059682

    • details UrineExpected but not Quantified Not AvailableNot AvailableTaking drug identified by DrugBank entry DB06287

  • 21059682

    • details

    Abnormal Concentrations

    Not Available Associated Disorders and Diseases Disease References

    None Associated OMIM IDs

    None External Links DrugBank ID

    DB06287 DrugBank Metabolite ID

    Not Available Phenol Explorer Compound ID

    Not Available Phenol Explorer Metabolite ID

    Not Available FoodDB ID

    Not Available KNApSAcK ID

    Not Available Chemspider ID

    21468899 KEGG Compound ID

    C15182 BioCyc ID

    Not Available BiGG ID

    Not Available Wikipedia Link

    Temsirolimus NuGOwiki Link

    HMDB15632 Metagene Link

    HMDB15632 METLIN ID

    Not Available PubChem Compound

    6918289 PDB ID

    Not Available ChEBI ID

    775133

    Product: Alverine (citrate)

    References Synthesis Reference Not Available Material Safety Data Sheet (MSDS) Not Available General References
    1. Shuuin T, Karashima H: [Mammalian target of rapamycin, its mode of action and clinical response in metastatic clear cell carcinoma]. Gan To Kagaku Ryoho. 2009 Jul;36(7):1076-9. [PubMed:19620795 ]
    2. Boni J, Leister C, Burns J, Cincotta M, Hug B, Moore L: Pharmacokinetic profile of temsirolimus with concomitant administration of cytochrome p450-inducing medications. J Clin Pharmacol. 2007 Nov;47(11):1430-9. Epub 2007 Oct 3. [PubMed:17913896 ]
    3. Mounier N, Vignot S, Spano JP: [Update on clinical activity of CCI779 (temsirolimus), mTOR inhibitor]. Bull Cancer. 2006 Nov;93(11):1139-43. [PubMed:17145584 ]
    4. (). Wyeth Pharmaceuticals Inc. Torisel® (temsirolimus) injection prescribing information. Philadelphia, PA: 2010 Sep.. .

    Enzymes

    General function:
    Involved in monooxygenase activity
    Specific 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.
    Gene Name:
    CYP3A4
    Uniprot ID:
    P08684
    Molecular weight:
    57255.585
    General function:
    Involved in monooxygenase activity
    Specific function:
    Responsible for the metabolism of many drugs and environmental chemicals that it oxidizes. It is involved in the metabolism of drugs such as antiarrhythmics, adrenoceptor antagonists, and tricyclic antidepressants.
    Gene Name:
    CYP2D6
    Uniprot ID:
    P10635
    Molecular weight:
    55768.94
    General function:
    Involved in monooxygenase activity
    Specific 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 oxidizes a variety of structurally unrelated compounds, including steroids, fatty acids, and xenobiotics.
    Gene Name:
    CYP3A5
    Uniprot ID:
    P20815
    Molecular weight:
    57108.065
    General function:
    Involved in monooxygenase activity
    Specific 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 oxidizes a variety of structurally unrelated compounds, including steroids, fatty acids, and xenobiotics.
    Gene Name:
    CYP3A7
    Uniprot ID:
    P24462
    Molecular weight:
    57525.03
    General function:
    Involved in binding
    Specific function:
    Kinase subunit of both mTORC1 and mTORC2, which regulate cell growth and survival in response to nutrient and hormonal signals. mTORC1 is activated in response to growth factors or amino-acids. Amino-acid-signaling to mTORC1 is mediated by Rag GTPases, which cause amino-acid-induced relocalization of mTOR within the endomembrane system. Growth factor-stimulated mTORC1 activation involves AKT1-mediated phosphorylation of TSC1-TSC2, which leads to the activation of the RHEB GTPase that potently activates the protein kinase activity of mTORC1. Activated mTORC1 up-regulates protein synthesis by phosphorylating key regulators of mRNA translation and ribosome synthesis. mTORC1 phosphorylates EIF4EBP1 and releases it from inhibiting the elongation initiation factor 4E (eiF4E). mTORC1 phosphorylates and activates S6K1 at Thr-421, which then promotes protein synthesis by phosphorylating PDCD4 and targeting it for degradation. mTORC2 is also activated by growth factors, but seems to be nutrient- insensitive. mTORC2 seems to function upstream of Rho GTPases to regulate the actin cytoskeleton, probably by activating one or more Rho-type guanine nucleotide exchange factors. mTORC2 promotes the serum-induced formation of stress-fibers or F-actin. mTORC2 plays a critical role in AKT1 Ser-473 phosphorylation, which may facilitate the phosphorylation of the activation loop of AKT1 on Thr-308 by PDK1 which is a prerequisite for full activation. mTORC2 regulates the phosphorylation of SGK1 at Ser-422. mTORC2 also modulates the phosphorylation of PRKCA on Ser-657
    Gene Name:
    MTOR
    Uniprot ID:
    P42345
    Molecular weight:
    288889.0
    References
    1. Patard JJ, Pouessel D, Bensalah K, Culine S: Targeted therapy in renal cell carcinoma. World J Urol. 2008 Apr;26(2):135-40. doi: 10.1007/s00345-008-0237-4. Epub 2008 Feb 12. [PubMed:18265991 ]
    2. Radulovic S, Bjelogrlic SK: Sunitinib, sorafenib and mTOR inhibitors in renal cancer. J BUON. 2007 Sep;12 Suppl 1:S151-62. [PubMed:17935273 ]
    3. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [PubMed:11752352 ]

    Transporters

    General function:
    Involved in ATP binding
    Specific function:
    Energy-dependent efflux pump responsible for decreased drug accumulation in multidrug-resistant cells
    Gene Name:
    ABCB1
    Uniprot ID:
    P08183
    Molecular weight:
    141477.3

    PMID: 23136043

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