VS-5584
VS-5584 Basic information
- Product Name:
- VS-5584
- Synonyms:
-
- 2-Pyrimidinamine, 5-[8-methyl-9-(1-methylethyl)-2-(4-morpholinyl)-9H-purin-6-yl]-
- 5-[8-Methyl-9-(1-methylethyl)-2-(4-morpholinyl)-9H-purin-6-yl]-2-pyrimidinamine VS-5584
- VS-5584, >=98%
- VS-5584
- SB 2343
- SB2343
- SB-2343
- VS-5584 (SB2343)
- CAS:
- 1246560-33-7
- MF:
- C17H22N8O
- MW:
- 354.41
- Product Categories:
-
- Akt
- mTOR
- PI3K
- PI3K/Akt/mTOR
- Inhibitors
- Mol File:
- 1246560-33-7.mol
VS-5584 Chemical Properties
- Boiling point:
- 687.2±65.0 °C(Predicted)
- Density
- 1.48±0.1 g/cm3(Predicted)
- storage temp.
- Store at -20°C
- solubility
- insoluble in H2O; ≥17.7 mg/mL in DMSO; ≥4.71 mg/mL in EtOH with ultrasonic
- form
- solid
- pka
- 4.53±0.10(Predicted)
- color
- Light yellow to yellow
- InChI
- InChI=1S/C17H22N8O/c1-10(2)25-11(3)21-14-13(12-8-19-16(18)20-9-12)22-17(23-15(14)25)24-4-6-26-7-5-24/h8-10H,4-7H2,1-3H3,(H2,18,19,20)
- InChIKey
- QYBGBLQCOOISAR-UHFFFAOYSA-N
- SMILES
- C1(N)=NC=C(C2=C3C(=NC(N4CCOCC4)=N2)N(C(C)C)C(C)=N3)C=N1
VS-5584 Usage And Synthesis
Description
Phosphatidylinositol 3-kinase (PI3K) signaling through Akt/PKB and the mammalian target of rapamycin (mTOR) controls gene expression related to cell proliferation, differentiation, and apoptosis. Increased activity of this pathway is important in many types of cancer. VS-5584 is a purine analog that inhibits mTOR (IC50 = 37 nM) and PI3K (IC50s = 16, 68, 25, and 42 nM for the α, β, γ, and δ isoforms, respectively) without relevant activity against more than 400 additional lipid and protein kinases. By inhibiting the phosphorylation of substrates downstream of PI3K and mTOR, VS-5584 demonstrates broad anti-proliferative sensitivity leading to tumor growth inhibition in human tumor models.
Uses
VS-5584 is a pan-PI3K/mTOR kinase inhibitor with IC50s of 16 nM, 68 nM, 42 nM, 25 nM, and 37 nM for PI3Kα, PI3Kβ, PI3Kδ, PI3Kγ and mTOR, respectively. VS-5584 simultaneously blocks mTORC2 as well as mTORC1.
in vivo
Nude mice bearing MDA-MB-231 human breast cancer tumors are treated for 5 days with once daily oral VS-5584 (25 mg/kg). Oral treatment of tumor bearing mice with VS-5584 reduces cancer atem cells analyzed from extracted tumors. Mice are implanted with tumor fragments from a docetaxel-resistant patient-derived triple negative breast cancer. Mice are treated with VS-5584 (20 mg/kg, po, qd) or Docetaxel (20 mg/kg, i.v.). Oral VS-5584 induces tumor regression in a Docetaxel-resistant patient-derived breast cancer model[1]. A single oral dose of VS-5584 is rapidly absorbed with a tmax of 0.9 hours and an elimination half-life of 10 hours. To determine the pharmacokinetic and pharmacodynamic relationship in tumors, PC3-tumor–bearing mice are treated with a single dose of VS-5584 and plasma and tumors are harvested after 6 hours and analyzed for concentrations of VS-5584 and effects on target efficacy biomarkers. Plasma levels of VS-5584 increase dose-dependently. For evaluation of efficacy in a Rapamycin-sensitive PC3 engraftment model, tumor-bearing mice are treated with VS-5584 for 28 days in comparison with the rapalog Everolimus. VS-5584 is well tolerated at both doses tested (11 and 25 mg/kg) with minimal weight loss (mean 4.7% on day 27). Treatment with VS-5584 leads to significant tumor growth inhibition (TGI) of 79% and 113% for 11 and 25 mg/kg, respectively[1].
target
mTOR
IC 50
PI3Kα: 16 nM (IC50); PI3Kγ: 25 nM (IC50); PI3Kδ: 42 nM (IC50); PI3Kβ: 68 nM (IC50); Vps34: 7470 nM (IC50); mTOR: 37 nM (IC50); mTORC1; mTORC2; DNA-PK: 1270 nM (IC50)
References
[1] Hart S, et al. VS-5584, a novel and highly selective PI3K/mTOR kinase inhibitor for the treatment of cancer. Mol Cancer Ther, 2013, 12(2), 151-161. DOI:10.1158/1535-7163.MCT-12-0466
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