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

Stem definition	Drug id	CAS RN
immunosuppressants, rapamycin derivatives	4161	162635-04-3

Description:

Molecule	Description
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

Molecule

Description

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:

Property	Value	Reference
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 µM/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:

Date	Agency	Company	Orphan
Nov. 19, 2007	EMA	Pfizer Limited
May 30, 2007	FDA	PF PRISM CV

FDA Adverse Event Reporting System (Female)

MedDRA adverse event term	Likelihood ratio	Likelihood ratio threshold	Patients taking drug having adverse event	Patients taking drug not having adverse event	Patients not taking drug having adverse event	Patients 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 term	Likelihood ratio	Likelihood ratio threshold	Patients taking drug having adverse event	Patients taking drug not having adverse event	Patients not taking drug having adverse event	Patients 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:

Source	Code	Description
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)

Disease	Relation	SNOMED_ID	DOID
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 level	Dissociation constant	Type (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:

Target	Class	Pharos	UniProt	Action	Type	Activity value (-log[M])	Bioact source	MoA source
Peptidyl-prolyl cis-trans isomerase FKBP1A	Enzyme	P62942	FKB1A_HUMAN	INHIBITOR			CHEMBL	CHEMBL
Peptidyl-prolyl cis-trans isomerase FKBP3	Enzyme	Q00688	FKBP3_HUMAN				WOMBAT-PK
Multidrug resistance protein 1	Transporter	P08183	MDR1_HUMAN				WOMBAT-PK
Serine/threonine-protein kinase mTOR	Kinase	P42345	MTOR_HUMAN		IC50	5.75	CHEMBL

External reference:

ID	Source
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