DrugBank: Temsirolimus (DB06287)

targets (1) enzymes (4) transporters (1)

Identification

Name

Temsirolimus

Accession Number

DB06287

Type

small molecule

Groups

approved

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

Download: MOL | SDF | SMILES | InChI
Display: 2D Structure | 3D Structure

Synonyms

CCI-779
temsirolimus

Brand names

Torisel

Brand name mixtures

Not Available

Categories

Antineoplastic Agents
Protein Kinase Inhibitors

CAS number

162635-04-3

Weight

Average: 1030.2871
Monoisotopic: 1029.602485741

Chemical Formula

C₅₆H₈₇NO₁₆

InChI Key

InChIKey=CBPNZQVSJQDFBE-FUXHJELOSA-N

InChI

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

Plain Text

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[30.3.1.0^{4,9}]hexatriaconta-16,24,26,28-tetraen-12-yl]propyl]-2-methoxycyclohexyl 3-hydroxy-2-(hydroxymethyl)-2-methylpropanoate

SMILES

[H][C@@]12CC[C@@H](C)[C@@](O)(O1)C(=O)C(=O)N1CCCC[C@H]1C(=O)O[C@@]([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=C\C=C\C=C(C)\[C@H](C2)OC)[C@H](C)C[C@@H]1CC[C@@H](OC(=O)C(C)(CO)CO)[C@@H](C1)OC

Plain Text

Mass Spec

Not Available

Taxonomy

Kingdom

Organic

Classes

Carbonyl Compounds
Pyrans
Amino Acids
Lactams
Piperidines

Substructures

Carbonyl Compounds
Carboxylic Acids and Derivatives
Hydroxy Compounds
Alkanes and Alkenes
Pyrans
Acetates
Lactones
Amino Ketones
Acetals and Derivatives
Ethers
Aliphatic and Aryl Amines
Alcohols and Polyols
Heterocyclic compounds
Carboxamides and Derivatives
Amino Acids
Lactams
Piperidines
Ketones

Pharmacology

Indication

For the treatment of renal cell carcinoma (RCC). Also investigated for use/treatment in breast cancer, lymphoma (unspecified), rheumatoid arthritis, and multiple myeloma.

Pharmacodynamics

Not Available

Mechanism of action

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.

Absorption

Infused intravenous over 30 - 60 minutes. C_max is typically observed at the end of infusion

Volume of distribution

172 L in whole blood of cancer patients; both temsirolimus and sirolimus are extensive distributed partitioned into formed blood elements

Protein binding

87% bound to plasma proteins in vitro at a concentration of 100 ng/ml

Metabolism

Primarily metabolized by cytochrome P450 3A4 in the human liver. Sirolimus, an equally potent metabolite, is the primary metabolite in humans following IV infusion. Other metabolic pathways observed in in vitro temsirolimus metabolism studies include hydroxylation, reduction and demethylation.

Route of elimination

Excreted predominantly in feces (76%), 4.6% of drug and metabolites recovered in urine. 17% of drug was not recovered by either route following a 14-day sample collection.

Half life

Temsirolimus exhibits a bi-exponential decline in whole blood concentrations and the mean half-lives of temsirolimus and sirolimus were 17.3 hr and 54.6 hr, respectively.

Clearance

16.2 L/h (22%)

Toxicity

Temsirolimus has been administered to patients with cancer in phase 1 and 2 trials with repeated intravenous doses as high as 220 mg/m2. The risk of several serious adverse events, including thrombosis, bowel perforation, interstitial lung disease (ILD), seizure, and psychosis, is increased with doses of temsirolimus greater than 25 mg.

Affected organisms

Humans and other mammals

Pathways

Not Available

Pharmacoeconomics

Manufacturers

Wyeth pharmaceuticals inc

Packagers

Dosage forms

Form	Route	Strength
Solution	Intravenous	25 mg/mL

Prices

Unit description	Cost	Unit
Torisel 25 mg kit	1467.89 USD	ml

Patents

Country	Patent Number	Approved	Expires
United States	5362718	1994-04-18	2014-04-18
Canada	2429020	2009-05-26	2021-11-13
Canada	2187024	2004-08-10	2015-04-14

Properties

State

solid

Melting point

Not Available

Experimental Properties

Not Available

Predicted Properties

Property	Value	Source
water solubility	2.35e-03 g/l	ALOGPS
logP	4.39	ALOGPS
logP	7.13	ChemAxon Molconvert
logS	-5.64	ALOGPS
pKa	13.40	ChemAxon Molconvert
hydrogen acceptor count	14	ChemAxon Molconvert
hydrogen donor count	4	ChemAxon Molconvert
polar surface area	241.96	ChemAxon Molconvert
rotatable bond count	11	ChemAxon Molconvert
refractivity	277.07	ChemAxon Molconvert
polarizability	112.71	ChemAxon Molconvert

References

Synthesis Reference

Not Available

General Reference

Wyeth Pharmaceuticals Inc. Torisel® (temsirolimus) injection prescribing information. Philadelphia, PA: 2010 Sep.
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

External Links

Resource	Link
KEGG Drug	D06068
KEGG Compound	C15182
PubChem Compound	23724530
PubChem Substance	99443243
ChemSpider	21468899
Therapeutic Targets Database	DAP001222
Drug Product Database	0
RxList	http://www.rxlist.com/cgi/generic/torisel.htm
Drugs.com	http://www.drugs.com/cdi/temsirolimus.html
Wikipedia	http://en.wikipedia.org/wiki/Temsirolimus

ATC Codes

L01XE09

AHFS Codes

10:00

PDB Entries

Not Available

FDA label

show (401.7 KB)

MSDS

Not Available

Interactions

Drug Interactions

Not Available

Food Interactions

Not Available

Targets
1. Serine/threonine-protein kinase mTOR Pharmacological action: yes Actions: inhibitor Acts as the target for the cell-cycle arrest and immunosuppressive effects of the FKBP12-rapamycin complex Organism class: human UniProt ID: P42345 Gene: FRAP1 Protein Sequence: FASTA Gene Sequence: FASTA SNPs: SNPJam Report References: Patard JJ, Pouessel D, Bensalah K, Culine S: Targeted therapy in renal cell carcinoma. World J Urol. 2008 Apr;26(2):135-40. Epub 2008 Feb 12. Pubmed Radulovic S, Bjelogrlic SK: Sunitinib, sorafenib and mTOR inhibitors in renal cancer. J BUON. 2007 Sep;12 Suppl 1:S151-62. Pubmed Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. Pubmed

Targets

1. Serine/threonine-protein kinase mTOR

Pharmacological action: yes
Actions: inhibitor

Acts as the target for the cell-cycle arrest and immunosuppressive effects of the FKBP12-rapamycin complex

Organism class: human
UniProt ID: P42345 Link_out

Gene: FRAP1 Link_out

Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:

Patard JJ, Pouessel D, Bensalah K, Culine S: Targeted therapy in renal cell carcinoma. World J Urol. 2008 Apr;26(2):135-40. Epub 2008 Feb 12. Pubmed
Radulovic S, Bjelogrlic SK: Sunitinib, sorafenib and mTOR inhibitors in renal cancer. J BUON. 2007 Sep;12 Suppl 1:S151-62. Pubmed
Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. Pubmed

Enzymes
1. Cytochrome P450 3A4 Actions: substrate, inhibitor 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. The enzyme also hydroxylates etoposide UniProt ID: P08684 Gene: CYP3A4 Protein Sequence: FASTA Gene Sequence: FASTA SNPs: SNPJam Report References: Flockhart DA. Drug Interactions: Cytochrome P450 Drug Interaction Table. Indiana University School of Medicine (2007). Accessed May 28, 2010. Wyeth Pharmaceuticals Inc. Torisel® (temsirolimus) injection prescribing information. Philadelphia, PA: 2010 Sep. 2. Cytochrome P450 3A5 Actions: substrate, inhibitor 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 UniProt ID: P20815 Gene: CYP3A5 Protein Sequence: FASTA Gene Sequence: FASTA SNPs: SNPJam Report References: Flockhart DA. Drug Interactions: Cytochrome P450 Drug Interaction Table. Indiana University School of Medicine (2007). Accessed May 28, 2010. Wyeth Pharmaceuticals Inc. Torisel® (temsirolimus) injection prescribing information. Philadelphia, PA: 2010 Sep. 3. Cytochrome P450 3A7 Actions: substrate 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 UniProt ID: P24462 Gene: CYP3A7 Protein Sequence: FASTA Gene Sequence: FASTA SNPs: SNPJam Report References: Flockhart DA. Drug Interactions: Cytochrome P450 Drug Interaction Table. Indiana University School of Medicine (2007). Accessed May 28, 2010. 4. Cytochrome P450 2D6 Actions: inhibitor 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 UniProt ID: P10635 Gene: CYP2D6 Protein Sequence: FASTA Gene Sequence: FASTA SNPs: SNPJam Report References: Wyeth Pharmaceuticals Inc. Torisel® (temsirolimus) injection prescribing information. Philadelphia, PA: 2010 Sep.

Enzymes

1. Cytochrome P450 3A4

Actions: substrate, inhibitor

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. The enzyme also hydroxylates etoposide

UniProt ID: P08684 Link_out

Gene: CYP3A4
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:

Flockhart DA. Drug Interactions: Cytochrome P450 Drug Interaction Table. Indiana University School of Medicine (2007). Accessed May 28, 2010.
Wyeth Pharmaceuticals Inc. Torisel® (temsirolimus) injection prescribing information. Philadelphia, PA: 2010 Sep.

2. Cytochrome P450 3A5

Actions: substrate, inhibitor

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

UniProt ID: P20815 Link_out

Gene: CYP3A5 Link_out

Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:

Flockhart DA. Drug Interactions: Cytochrome P450 Drug Interaction Table. Indiana University School of Medicine (2007). Accessed May 28, 2010.
Wyeth Pharmaceuticals Inc. Torisel® (temsirolimus) injection prescribing information. Philadelphia, PA: 2010 Sep.

3. Cytochrome P450 3A7

Actions: substrate

UniProt ID: P24462 Link_out

Gene: CYP3A7 Link_out

Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:

Flockhart DA. Drug Interactions: Cytochrome P450 Drug Interaction Table. Indiana University School of Medicine (2007). Accessed May 28, 2010.

4. Cytochrome P450 2D6

Actions: inhibitor

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

UniProt ID: P10635 Link_out

Gene: CYP2D6 Link_out

Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:

Wyeth Pharmaceuticals Inc. Torisel® (temsirolimus) injection prescribing information. Philadelphia, PA: 2010 Sep.

Transporters
1. Multidrug resistance protein 1 Actions: substrate, inhibitor Energy-dependent efflux pump responsible for decreased drug accumulation in multidrug-resistant cells UniProt ID: P08183 Gene: ABCB1 Protein Sequence: FASTA Gene Sequence: FASTA SNPs: SNPJam Report References: Wyeth Pharmaceuticals Inc. Torisel® (temsirolimus) injection prescribing information. Philadelphia, PA: 2010 Sep.

Comments

Drug created on March 19, 2008 10:22 / Updated on November 28, 2010 14:08

This project is supported by Genome Alberta & Genome Canada, a not-for-profit organization that is leading Canada's national genomics strategy with $600 million in funding from the federal government. This project is also supported in part by GenomeQuest, Inc., an enterprise genomic information company serving the life science community.