Target Validation Information
Target ID T75243
Target Name Serine/threonine-protein kinase mTOR
Target Type
Successful
Drug Potency against Target Everolimus Drug Info IC50 = 5~6 nM [553040]
(4-(6-morpholino-9H-purin-2-yl)phenyl)methanol Drug Info IC50 = 4500 nM [530563]
2-Morpholin-4-yl-pyrimido[2,1-a]isoquinolin-4-one Drug Info IC50 = 5300 nM [527386]
2-(6-morpholino-9H-purin-2-yl)phenol Drug Info IC50 = 2500 nM [530563]
4-(2-(thiophen-2-yl)-9H-purin-6-yl)morpholine Drug Info IC50 = 2800 nM [530563]
4-(2-(thiophen-3-yl)-9H-purin-6-yl)morpholine Drug Info IC50 = 3900 nM [530563]
3-(6-morpholino-9H-purin-2-yl)phenol Drug Info IC50 = 2383 nM [530563]
C-16-(S)-3-methylindolerapamycin Drug Info IC50 = 5 nM [528725]
Macrolide derivative Drug Info IC50 = 1.45 nM [527216]
Ridaforolimus Drug Info IC50 = 0.2~1.0 nmol [553096]
AP-21967 Drug Info IC50 = 10 nM [528725]
4-(2-(1H-indol-6-yl)-9H-purin-6-yl)morpholine Drug Info IC50 = 150 nM [530563]
4-(6-morpholino-9H-purin-2-yl)phenol Drug Info IC50 = 450 nM [530563]
2-(2-Methyl-morpholin-4-yl)-benzo[h]chromen-4-one Drug Info IC50 = 4800 nM [527386]
LY-293646 Drug Info IC50 = 6400 nM [527386]
Action against Disease Model Sirolimus We 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 ofcombination 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. [552464] Drug Info
References
Ref 553040Biomarker Development for the Clinical Activity of the mTOR Inhibitor Everolimus (RAD001): Processes, Limitations, and Further Proposals. Transl Oncol. 2010 Apr;3(2):65-79.
Ref 530563Bioorg 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.
Ref 527386J 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.
Ref 530563Bioorg 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.
Ref 530563Bioorg 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.
Ref 530563Bioorg 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.
Ref 530563Bioorg 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.
Ref 528725J 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.
Ref 527216J Med Chem. 2004 Sep 23;47(20):4950-7.A locally active antiinflammatory macrolide (MLD987) for inhalation therapy of asthma.
Ref 553096Ridaforolimus (AP23573; MK-8669), a potent mTOR inhibitor, has broad antitumor activity and can be optimally administered using intermittent dosing regimens. Mol Cancer Ther. 2011 Jun;10(6):1059-71. doi: 10.1158/1535-7163.MCT-10-0792. Epub 2011 Apr 11.
Ref 528725J 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.
Ref 552464Targeting mammalian target of rapamycin synergistically enhances chemotherapy-induced cytotoxicity in breast cancer cells. Clin Cancer Res. 2004 Oct 15;10(20):7031-42.
Ref 530563Bioorg 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.
Ref 530563Bioorg 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.
Ref 527386J 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.
Ref 527386J 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.

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