product name VS-5584 (SB2343)
Description: VS-5584 (also known as 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.
References: Mol Cancer Ther. 2013 Feb;12(2):151-61.
354.41
Formula
C17H22N8O
CAS No.
1246560-33-7
Storage
-20℃ for 3 years in powder form
-80℃ for 2 years in solvent
Solubility (In vitro)
DMSO: 71 mg/mL (200.3 mM)
Water: <1 mg/mL
Ethanol: 3 mg/mL (8.46 mM)
Solubility (In vivo)
0.5% methylcellulose+0.2% Tween 80: 30 mg/mL
Chemical Name
5-(8-methyl-2-morpholin-4-yl-9-propan-2-ylpurin-6-yl)pyrimidin-2-amine
other peoduct :
| In Vitro |
Kinase Assay: 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 Assay: 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). VS-5584 is an ATP-competitive inhibitor which selectively inhibits PI3K/mTOR signaling with equivalent low nanomolar potency against all human Class I PI3K isoforms and mTOR kinase. VS-5584 is approximately 10-fold selective for cancer stem cells with an EC50 of 15 nM in HMLE breast cancer cells. VS-5584 preferentially decreases CD44Hi/CD24Lo cells in an HMLER immortalized mammary cancer cell line. In SUM159 cells, VS-5584 effectively eliminates the cancer stem cell side population. A large human cancer cell line panel screen (436 lines) reveals broad antiproliferative sensitivity and that cells harboring mutations in PI3KCA are generally more sensitive toward VS-5584 treatment. In the FLT3-ITD harboring MV4-11 cells, VS-5584 blocks pAkt (S473) and pAkt (T308) with IC50 of 12 and 13 nM, respectively. The IC50 of VS-5584 for pS6 (S240/244), pAkt (S473), and pAkt (T308) are 20, 23, and 15 nM, respectively |
|---|---|
| In Vivo | In mice bearing triple negative breast cancer tumors, oral dosing of VS-5584 decreases tumor cancer stem cells and induces tumor regression in taxane-resistant models. In a PTENnull human prostate PC3 xenograft model, treatment with VS-5584 leads to significant tumor growth inhibition (TGI) of 79% and 113% for 11 and 25 mg/kg, respectively. In a FLT3-ITD AML xenograft model, VS-5584 treatment induces dose-dependent inhibition of tumor growth (28% for 3.7 mg/kg and 76% for 11 mg/kg). |
| Animal model | PTENnull human prostate PC3 xenograft model |
| Formulation & Dosage | 0.5% methylcellulose (w/v) and 0.1% Tween-80 in H2O (MC/Tween); 11, 25 mg/kg; oral administration |
| References | [1] Hart S, et al. Mol Cancer Ther, 2013, 12(2), 151-161. |
