temsirolimus Indications/Contra | FAERs-F | FAERs-M | Orange Bk | BioActivity |

Stem definitionDrug idCAS RN
immunosuppressants, rapamycin derivatives 4161 162635-04-3

Description:

MoleculeDescription

Molfile Inchi Smiles

Synonyms:

  • temsirolimus
  • torisel
  • temsorolimus
  • CCI-779
  • CCI 779
Temsirolimus is an inhibitor of mTOR (mammalian target of rapamycin). Temsirolimus binds to an intracellular protein (FKBP-12), and the protein-drug complex inhibits the activity of mTOR that controls cell division. Inhibition of mTOR activity resulted in a G1 growth arrest in treated tumor cells. When mTOR was inhibited, its ability to phosphorylate p70S6k and S6 ribosomal protein, which are downstream of mTOR in the PI3 kinase/AKT pathway was blocked. In in vitro studies using renal cell carcinoma cell lines, temsirolimus inhibited the activity of mTOR and resulted in reduced levels of the hypoxia-inducible factors HIF-1 and HIF-2 alpha, and the vascular endothelial growth factor.
  • Molecular weight: 1030.30
  • Formula: C56H87NO16
  • CLOGP: 7.46
  • LIPINSKI: 3
  • HAC: 17
  • HDO: 4
  • TPSA: 241.96
  • ALOGS: -5.64
  • ROTB: 11

  • Status: OFP

  • Legend:
    OFP - off patent
    OFM - off market
    ONP - on patent

Drug dosage:

None

ADMET properties:

PropertyValueReference
BDDCS (Biopharmaceutical Drug Disposition Classification System) 1 Benet LZ, Broccatelli F, Oprea TI
S (Water solubility) 0.01 mg/mL Benet LZ, Broccatelli F, Oprea TI
EoM (Fraction excreted unchanged in urine) 4.60 % Benet LZ, Broccatelli F, Oprea TI
MRTD (Maximum Recommended Therapeutic Daily Dose) 0.15 ┬ÁM/kg/day Contrera JF, Matthews EJ, Kruhlak NL, Benz RD
Vd (Volume of distribution) 3 L/kg Lombardo F, Berellini G, Obach RS
CL (Clearance) 7.70 mL/min/kg Lombardo F, Berellini G, Obach RS
t_half (Half-life) 18 hours Lombardo F, Berellini G, Obach RS

Approvals:

DateAgencyCompanyOrphan
Nov. 19, 2007 EMA Pfizer Limited
May 30, 2007 FDA PF PRISM CV

FDA Adverse Event Reporting System (Female)

MedDRA adverse event termLikelihood ratioLikelihood ratio thresholdPatients taking drug having adverse eventPatients taking drug not having adverse eventPatients not taking drug having adverse eventPatients not taking drug not having adverse event
Disease progression 244.62 31.42 113 2491 91187 46592271
Renal cell carcinoma 126.14 31.42 31 2573 3507 46679951
Metastatic renal cell carcinoma 80.98 31.42 17 2587 946 46682512
Hyperglycaemia 56.77 31.42 31 2573 35040 46648418
Dehydration 43.80 31.42 49 2555 159491 46523967
Hypophosphataemia 43.05 31.42 16 2588 7351 46676107
Mucosal inflammation 40.80 31.42 26 2578 38950 46644508
Hypokalaemia 38.83 31.42 35 2569 87989 46595469
Stomatitis 37.94 31.42 31 2573 68266 46615192
Death 36.33 31.42 66 2538 335482 46347976
Hypertriglyceridaemia 35.58 31.42 13 2591 5691 46677767
Pneumonitis 34.92 31.42 21 2583 28399 46655059

FDA Adverse Event Reporting System (Male)

MedDRA adverse event termLikelihood ratioLikelihood ratio thresholdPatients taking drug having adverse eventPatients taking drug not having adverse eventPatients not taking drug having adverse eventPatients not taking drug not having adverse event
Disease progression 502.11 21.90 261 5429 79613 29867175
Renal cell carcinoma 264.92 21.90 80 5610 5686 29941102
Metastatic renal cell carcinoma 179.02 21.90 49 5641 2443 29944345
Interstitial lung disease 91.42 21.90 82 5608 60115 29886673
Neoplasm progression 90.38 21.90 51 5639 17972 29928816
Pneumonitis 80.00 21.90 55 5635 27399 29919389
Stomatitis 69.18 21.90 57 5633 37222 29909566
Pleural effusion 66.60 21.90 76 5614 73990 29872798
Mucosal inflammation 43.19 21.90 40 5650 30454 29916334
Dehydration 43.10 21.90 81 5609 123458 29823330
Thrombocytopenia 41.92 21.90 85 5605 136959 29809829
Renal cancer 39.58 21.90 18 5672 4022 29942766
Neoplasm malignant 36.74 21.90 29 5661 17785 29929003
Mantle cell lymphoma 36.62 21.90 13 5677 1528 29945260
Pneumocystis jirovecii pneumonia 33.45 21.90 27 5663 17093 29929695
Hypertriglyceridaemia 30.33 21.90 19 5671 8079 29938709
Drug ineffective 27.96 21.90 15 5675 340372 29606416
Pneumonia 25.59 21.90 128 5562 334178 29612610
Febrile neutropenia 25.53 21.90 60 5630 106633 29840155
Blood triglycerides increased 25.06 21.90 21 5669 13996 29932792
Extravasation 23.96 21.90 10 5680 1818 29944970
Osteonecrosis of jaw 23.63 21.90 23 5667 18595 29928193

Pharmacologic Action:

SourceCodeDescription
ATC L01EG01 ANTINEOPLASTIC AND IMMUNOMODULATING AGENTS
ANTINEOPLASTIC AGENTS
PROTEIN KINASE INHIBITORS
Mammalian target of rapamycin (mTOR) kinase inhibitors
FDA MoA N0000175076 Protein Kinase Inhibitors
FDA EPC N0000175605 Kinase Inhibitor

Drug Use (View source of the data)

DiseaseRelationSNOMED_IDDOID
Mantle cell lymphoma indication 443487006
Renal cell carcinoma indication 702391001 DOID:4450
Hyperbilirubinemia contraindication 14783006 DOID:2741
Gastrointestinal perforation contraindication 51875005
Hyperlipidemia contraindication 55822004 DOID:1168
Acute infectious disease contraindication 63171007
Interstitial pneumonia contraindication 64667001
Diabetes mellitus contraindication 73211009 DOID:9351
Hyperglycemia contraindication 80394007 DOID:4195
Kidney disease contraindication 90708001 DOID:557
Secondary malignant neoplasm of cerebrum contraindication 94248000
Perioperative care contraindication 133897009
Cerebrovascular accident contraindication 230690007
Disease of liver contraindication 235856003 DOID:409
Impaired wound healing contraindication 271618001
Pregnancy, function contraindication 289908002
Surgical procedure contraindication 387713003
Breastfeeding (mother) contraindication 413712001
Malignant neoplasm of brain contraindication 428061005 DOID:1319

Acid dissociation constants calculated using MoKa v3.0.0

Dissociation levelDissociation constantType (acidic/basic)
pKa1 10.5 acidic
pKa2 13.82 acidic

Orange Book patent data (new drug applications)

None

Orange Book exclusivity data (new drug applications)

None

Bioactivity Summary:

TargetClassPharosUniProtActionTypeActivity value
(-log[M])
Mechanism
action
Bioact sourceMoA source
Peptidyl-prolyl cis-trans isomerase FKBP1A Enzyme INHIBITOR CHEMBL CHEMBL
Peptidyl-prolyl cis-trans isomerase FKBP3 Enzyme WOMBAT-PK
Multidrug resistance protein 1 Transporter WOMBAT-PK
Serine/threonine-protein kinase mTOR Kinase IC50 5.75 CHEMBL

External reference:

IDSource
4026239 VUID
N0000179796 NUI
D06068 KEGG_DRUG
4026239 VANDF
C0796512 UMLSCUI
CHEBI:79699 CHEBI
CHEMBL1201182 ChEMBL_ID
C401859 MESH_SUPPLEMENTAL_RECORD_UI
6918289 PUBCHEM_CID
8212 INN_ID
DB06287 DRUGBANK_ID
624KN6GM2T UNII
5892 IUPHAR_LIGAND_ID
657797 RXNORM
110527 MMSL
23908 MMSL
287829 MMSL
d06836 MMSL
012233 NDDF
427153004 SNOMEDCT_US
427299005 SNOMEDCT_US

Pharmaceutical products:

None