A selective PI3K/mTOR kinase inhibitor
VS-5584 (SB2343), a purine analog, is a novel small-molecule inhibitor of both mammalian target of rapamycin (mTOR) kinase and all class I phosphoinostide 3-kinase (PI3K) isoforms that ATP-competitively inhibits the activity of mTOR, PI3Kα, PI3Kβ, PI3Kγ and PI3Kδ with values of 50% inhibition concentration IC50 of 37 nmol/L, 16 nmol/L, 68 nmol/L, 25 nmol/L and 42 nmol/L respectively. VS-5585 robustly modulates the cellular PI3K/mTOR pathway, one of the most commonly activated signaling pathways in human cancer, through inhibition of phosphorylation of substrates downstream of PI3K and mTORC1/2. Moreover, VS-5584 has been found to dose-dependently inhibit PI3K/mTOR signaling in tumor tissue resulting in tumor growth inhibition in human xengograft models.
Reference
Hart S, Novotny-Diermayr V, Goh KC, Williams M, Tan YC, Ong LC, Cheong A, Ng BK, Amalini C, Madan B, Nagaraj H, Jayaraman R, Pasha KM, Ethirajulu K, Chng WJ, Mustafa N, Goh BC, Benes C, McDermott U, Garnett M, Dymock B, Wood JM. VS-5584, a novel and highly selective PI3K/mTOR kinase inhibitor for the treatment of cancer. Mol Cancer Ther. 2013 Feb;12(2):151-61. doi: 10.1158/1535-7163.MCT-12-0466. Epub 2012 Dec 27.
| Kinase experiment [1]: | |
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In vitro mTOR kinase assays |
The reaction mixture consisted of the following components in 10 μL assay buffer (50 mM Hepes pH 7.5, 10 mM MgCl2, 3 mM MnCl2, 1 mM EGTA, 2 mM DTT, 0.01%Tween-20): 0.10 μg/mL of in-house generated mTOR enzyme, 0.05 μM ULight-eIF4E-binding protein 1 (Thr37/46) peptide and 10 μM ATP. The mixture was incubated for 60 mins at room temperature. 10 μL of Detection mixture consisted of 16 mM EDTA, 0.004 mM Eu-W1024-labeled Anti-Phospho-eIF4E-binding protein 1-(Thr37/46) antibody and 1 × LANCE? Detection Buffer was then added and incubated for 60 mins. |
| Cell experiment [1]: | |
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Cell lines |
H929 cells |
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Preparation method |
The solubility of this compound in DMSO is >10 mM. General tips for obtaining a higher concentration: Please warm the tube at 37℃ for 10 minutes and/or shake it in the ultrasonic bath for a while. Stock solution can be stored below -20℃ for several months. |
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Reaction Conditions |
Up to 10 μM; 48 hrs |
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Applications |
VS-5584 showed high anti-proliferative activity in a broad spectrum of cancer cells, with H929 cells (multiple myeloma) exhibiting the highest sensitivity in our panel (IC50 = 48 nM). |
| Animal experiment [1]: | |
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Animal models |
PTENnull human prostate PC3 xenograft model |
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Dosage form |
11 or 25 mg/kg; p.o.; q.d., for 28 days |
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Applications |
In a PTENnull human prostate PC3 xenograft model, VS-5584 treatment led to significant tumor growth inhibition (TGI) of 79% and 113% for 11 and 25 mg/kg, respectively. |
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Other notes |
Please test the solubility of all compounds indoor, and the actual solubility may slightly differ with the theoretical value. This is caused by an experimental system error and it is normal. |
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参考文献: [1]. Hart S, Novotny-Diermayr V, Goh KC, Williams M, Tan YC, Ong LC, Cheong A, Ng BK, Amalini C, Madan B, Nagaraj H, Jayaraman R, Pasha KM, Ethirajulu K, Chng WJ, Mustafa N, Goh BC, Benes C, McDermott U, Garnett M, Dymock B, Wood JM. VS-5584, a novel and highly selective PI3K/mTOR kinase inhibitor for the treatment of cancer. Mol Cancer Ther. 2013 Feb;12(2):151-61. | |
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