Target Validation Information
TTD ID	T75243
Target Name	Serine/threonine-protein kinase mTOR (mTOR)
Type of Target	Successful
Drug Potency against Target	Everolimus	Drug Info	IC50 = 5~6 nM	[6]
	Ridaforolimus	Drug Info	IC50 = 0.2~1.0 nmol	[7]
		Drug Info	IC50 = 1.45 nM	[1]
	(4-(6-morpholino-9H-purin-2-yl)phenyl)methanol	Drug Info	IC50 = 4500 nM	[4]
	2-(2-Methyl-morpholin-4-yl)-benzo[h]chromen-4-one	Drug Info	IC50 = 4800 nM	[2]
	2-(6-morpholino-9H-purin-2-yl)phenol	Drug Info	IC50 = 2500 nM	[4]
	2-Morpholin-4-yl-pyrimido[2,1-a]isoquinolin-4-one	Drug Info	IC50 = 5300 nM	[2]
	3-(6-morpholino-9H-purin-2-yl)phenol	Drug Info	IC50 = 2383 nM	[4]
	4-(2-(1H-indol-6-yl)-9H-purin-6-yl)morpholine	Drug Info	IC50 = 150 nM	[4]
	4-(2-(thiophen-2-yl)-9H-purin-6-yl)morpholine	Drug Info	IC50 = 2800 nM	[4]
	4-(2-(thiophen-3-yl)-9H-purin-6-yl)morpholine	Drug Info	IC50 = 3900 nM	[4]
	4-(6-morpholino-9H-purin-2-yl)phenol	Drug Info	IC50 = 450 nM	[4]
	AP-21967	Drug Info	IC50 = 10 nM	[3]
	C-16-(S)-3-methylindolerapamycin	Drug Info	IC50 = 5 nM	[3]
	Ethyl 1-[(1H-benzimidazol-2(3H)one-5-yl)sulfonyl]-1H-pyrrole-2-carboxylate	Drug Info	IC50 = 6400 nM	[2]
Action against Disease Model	Sirolimus	Drug Info	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.	[5]
References
REF 1	A locally active antiinflammatory macrolide (MLD987) for inhalation therapy of asthma. J Med Chem. 2004 Sep 23;47(20):4950-7.
REF 2	Selective benzopyranone and pyrimido[2,1-a]isoquinolin-4-one inhibitors of DNA-dependent protein kinase: synthesis, structure-activity studies, and... J Med Chem. 2005 Jan 27;48(2):569-85.
REF 3	The rapamycin-binding domain of the protein kinase mammalian target of rapamycin is a destabilizing domain. J Biol Chem. 2007 May 4;282(18):13395-401.
REF 4	Novel purine and pyrazolo[3,4-d]pyrimidine inhibitors of PI3 kinase-alpha: Hit to lead studies. Bioorg Med Chem Lett. 2010 Jan 15;20(2):636-9.
REF 5	Targeting mammalian target of rapamycin synergistically enhances chemotherapy-induced cytotoxicity in breast cancer cells. Clin Cancer Res. 2004 Oct 15;10(20):7031-42.
REF 6	Biomarker 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 7	Ridaforolimus (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.

If You Find Any Error in Data or Bug in Web Service, Please Kindly Report It to Dr. Zhou and Dr. Zhang.