Therapeutic Targets Database
BIDD Pharmainformatics Databases
 
   
 

 

Target Validation Information
TTD IDTTDS00265
Target NameSerine/threonine-protein kinase mTOR    
Type of TargetSuccessful target    
Drug Potency against TargetTemsirolimusIC50 < 1 nM[1]
EverolimusIC50 < 1 nmol[2]
TemsirolimusIC50 = 1.76+/-0.15 nM[3]
EverolimusIC50 = 5~6 nM[4]
RidaforolimusIC50 = 0.2~1.0 nmol[5]
XL765IC50 = 157 nM[6]
Macrolide derivativeIC50 = 1.45 nM[7]
Macrolide derivativeIC50 = 1.88 nM[7]
AP-21967IC50 = 10 nM[8]
4-(2-(1H-indol-6-yl)-9H-purin-6-yl)morpholineIC50 = 150 nM[9]
3-(6-morpholino-9H-purin-2-yl)phenolIC50 = 2383 nM[9]
2-(6-morpholino-9H-purin-2-yl)phenolIC50 = 2500 nM[9]
LY-294002IC50 = 2500 nM[10]
4-(2-(thiophen-2-yl)-9H-purin-6-yl)morpholineIC50 = 2800 nM[9]
4-(2-(thiophen-3-yl)-9H-purin-6-yl)morpholineIC50 = 3900 nM[9]
4-(6-morpholino-9H-purin-2-yl)phenolIC50 = 450 nM[9]
(4-(6-morpholino-9H-purin-2-yl)phenyl)methanolIC50 = 4500 nM[9]
2-(2-Methyl-morpholin-4-yl)-benzo[h]chromen-4-oneIC50 = 4800 nM[10]
C-16-(S)-3-methylindolerapamycinIC50 = 5 nM[8]
2-Morpholin-4-yl-pyrimido[2,1-a]isoquinolin-4-oneIC50 = 5300 nM[10]
LY-293646IC50 = 6400 nM[10]
Action against Disease ModelSirolimusWe performed a multiple drug effect/combination index isobologram analysis in cells sensitive and resistant to rapamycin alone in vitro, and we evaluated the in vivo efficacy of combination therapy in a rapamycin-sensitive model.In vitro, synergistic interactions were observed in combinations with paclitaxel, carboplatin, and vinorelbine. Additive effects were observed in combinations with doxorubicin and gemcitabine. Rapamycin dramatically enhanced paclitaxel- and carboplatin-induced apoptosis. This effect was sequence dependent and mediated at least partly through caspase activation. Furthermore, rapamycin enhanced chemosensitivity to paclitaxel and carboplatin in HER2/neu-overexpressing cells, suggesting a potential approach to these poorly behaving t uMors. Cell lines that are resistant to the growth-inhibitory effect of rapamycin were also resistant to rapamycin-mediated chemosensitization. In vivo, rapamycin combined with paclitaxel resulted in a significant reduction in t uMor vol uMe compared with either agent alone in rapamycin-sensitive t uMors.[11]
Ref 1Cancer Sci. 2011 Jul;102(7):1344-9. doi: 10.1111/j.1349-7006.2011.01967.x. Epub 2011 Jun 2.Inhibition of mTOR by temsirolimus contributes to prolonged survival of mice with pleural dissemination of non-small-cell lung cancer cells. To Reference
Ref 2Clin Cancer Res. 2009 Mar 1;15(5):1612-22. Epub 2009 Feb 17.mTOR inhibitor RAD001 (everolimus) has antiangiogenic/vascular properties distinct from a VEGFR tyrosine kinase inhibitor. To Reference
Ref 3Cancer Res. 2008 Apr 15;68(8):2934-43.A new pharmacologic action of CCI-779 involves FKBP12-independent inhibition of mTOR kinase activity and profound repression of global protein synthesis. To Reference
Ref 4Transl Oncol. 2010 Apr;3(2):65-79.Biomarker Development for the Clinical Activity of the mTOR Inhibitor Everolimus (RAD001): Processes, Limitations, and Further Proposals. To Reference
Ref 5Mol Cancer Ther. 2011 Jun;10(6):1059-71. Epub 2011 Apr 11.Ridaforolimus (AP23573; MK-8669), a potent mTOR inhibitor, has broad antitumor activity and can be optimally administered using intermittent dosing regimens. To Reference
Ref 6XL765 Targets Tumor Growth, Survival, and Angiogenesis in Preclinical Models by Dual Inhibition of PI3K and mTOR. Company Report from EXELIXIS To Reference
Ref 7J Med Chem. 2004 Sep 23;47(20):4950-7.A locally active antiinflammatory macrolide (MLD987) for inhalation therapy of asthma. To Reference
Ref 8J Biol Chem. 2007 May 4;282(18):13395-401. Epub 2007 Mar 9.The rapamycin-binding domain of the protein kinase mammalian target of rapamycin is a destabilizing domain. To Reference
Ref 9Bioorg Med Chem Lett. 2010 Jan 15;20(2):636-9. Epub 2009 Dec 5.Novel purine and pyrazolo[3,4-d]pyrimidine inhibitors of PI3 kinase-alpha: Hit to lead studies. To Reference
Ref 10J Med Chem. 2005 Jan 27;48(2):569-85.Selective benzopyranone and pyrimido[2,1-a]isoquinolin-4-one inhibitors of DNA-dependent protein kinase: synthesis, structure-activity studies, and radiosensitization of a human tumor cell line in vitro. To Reference
Ref 11Clin Cancer Res. 2004 Oct 15;10(20):7031-42.Targeting mammalian target of rapamycin synergistically enhances chemotherapy-induced cytotoxicity in breast cancer cells. To Reference



 

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