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Purity: ≥98%
VS-5584 (also known as SB2343), a purine analog, is a novel, potent, and selective small-molecule dual inhibitor of both mTOR kinase and all class I phosphoinositide 3-kinase (PI3K) isoforms with potential anticancer activity. With IC50 values of 37 nmol/L, 16 nmol/L, 68 nmol/L, 25 nmol/L, and 42 nmol/L, respectively, it inhibits the activity of mTOR, PI3Kα, PI3Kβ, PI3Kγ and PI3Kδ by competing with ATP. By preventing the phosphorylation of substrates downstream of PI3K and mTORC1/2, VS-5585 effectively modulates the cellular PI3K/mTOR pathway, one of the signaling pathways that is most frequently activated in human cancer.
| Targets |
PI3Kα (IC50 = 16 nM); PI3Kγ (IC50 = 25 nM); PI3Kδ (IC50 = 42 nM); PI3Kβ (IC50 = 68 nM); Vps34 (IC50 = 7470 nM); mTOR (IC50 = 37 nM); DNA-PK (IC50 = 1270 nM); mTORC1; mTORC2
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| ln Vitro |
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. With an EC50 of 15 nM in HMLE breast cancer cells, VS-5584 is roughly 10-fold selective for cancer stem cells. In a HMLER immortalized mammary cancer cell line, VS-5584 preferentially reduces CD44Hi/CD24Lo cells. VS-5584 successfully eradicates the cancer stem cell side population in SUM159 cells. Wide-ranging antiproliferative sensitivity is found in a large human cancer cell line panel screen (436 lines), and cells with PI3KCA mutations are generally more responsive to VS-5584 treatment.
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| ln 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. Treatment with VS-5584 significantly inhibits tumor growth (TGI) in a PTENnull human prostate PC3 xenograft model by 79% and 113% for 11 and 25 mg/kg, respectively. A dose-dependent inhibition of tumor growth is brought about by VS-5584 treatment in a FLT3-ITD AML xenograft model (28% at 3.7 mg/kg and 76% at 11 mg/kg). [1]
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| Enzyme Assay |
The reaction mixture consisted of the following components in 10 μL assay buffer (50 mM Hepes pH 7.5, 10 mM MgCl 2, 3 mM MnCl 2, 1 mM EGTA, 2 mM DTT, 0.01%Tween-20): 10 μM ATP, 0.05 μM ULight-eIF4E-binding protein 1 (Thr37/46) peptide, and 0.10 μg/mL of house-made mTOR enzyme. At room temperature, the mixture is incubated for 60 minutes. Then, 1X LANCE® Detection Buffer and 10 μL of the detection mixture, which included 16 mM EDTA, 0.004 mM Eu-W1024-labeled Anti-Phospho-eIF4E-binding protein 1-(Thr37/46) antibody, are added. The mixture is then incubated for 60 min.
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| Cell Assay |
For proliferation assays in 96-well plates, SET-2, SNU-478, SNU-1196, SNU-245, SNU-1079, SNU-308, SNU-869, and MKN7 cells are used. The multiple myeloma cells (H929, MM1.S, MM1.R, R8226, U266) and nasopharyngeal cells (CNE-1, CNE-2, HONE1, HK1) are used. The following day, cells are treated with VS-5584 (in triplicates) at concentrations up to 10 μMfor 48 hours after being seeded at 30% to 50% confluency for adherent cells or 2,000 to 6,000 cells for suspension cells. The CellTiter-Glo assay is used to track cell viability. Using the XL-fit program, dose-response curves were plotted to determine the IC50 values for the compounds.
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| Animal Protocol |
Mice: Athymic BALB/c nude mice (BALB/cOlaHsd-Foxn1nu) are used. Fox-Chase severe combined immunodeficient (SCID) mice (CB17/Icr-Prkdcscid/CrlBltw) are used. The right flank of male (PC3 and COLO 205), female (MV4-11 and HuH7), or male (NCI-N87) BALB/c nude mice is intradermally implanted with 5106 (PC3, COLO205, HuH7, NCI-N87), or 1107 (MV4-11) cells. Using a 27.5-gauge needle, cells are resuspended in 70% (v/v; only for COLO205 and HuH7) or 50% (v/v) serum-free growth medium/Matrigel and injected in a total volume of 100 L. Dosing began seven to fourteen days after tumor implantation. Oral doses of VS-5584 (11 and 25 mg/kg) are administered daily[1].
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| References |
| Molecular Formula |
C17H22N8O
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|---|---|
| Molecular Weight |
354.40958
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| Exact Mass |
354.19166
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| Elemental Analysis |
C, 57.61; H, 6.26; N, 31.62; O, 4.51
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| CAS # |
1246560-33-7
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| Related CAS # |
1246560-33-7
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| Appearance |
White to off-white crystalline solid
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| SMILES |
CC1=NC2=C(N=C(N=C2N1C(C)C)N3CCOCC3)C4=CN=C(N=C4)N
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| InChi Key |
QYBGBLQCOOISAR-UHFFFAOYSA-N
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| InChi Code |
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)
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| Chemical Name |
5-(8-methyl-2-morpholin-4-yl-9-propan-2-ylpurin-6-yl)pyrimidin-2-amine
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| Synonyms |
VS5584; VS5584; VS 5584; SB2343; SB2343; SB 2343
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
DMSO: ~71 mg/mL (~200.3 mM)
Water: <1 mg/mL Ethanol: ~3 mg/mL (~8.5 mM) |
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (7.05 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 2.5 mg/mL (7.05 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. View More
Solubility in Formulation 3: ≥ 2.5 mg/mL (7.05 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. Solubility in Formulation 4: 0.5% methylcellulose+0.2%Tween 80: 30 mg/mL |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.8216 mL | 14.1080 mL | 28.2159 mL | |
| 5 mM | 0.5643 mL | 2.8216 mL | 5.6432 mL | |
| 10 mM | 0.2822 mL | 1.4108 mL | 2.8216 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
| NCT Number | Status | Interventions | Conditions | Sponsor/Collaborators | Start Date | Phases |
| NCT01991938 | Terminated | Drug: VS-5584 | Lymphoma Metastatic Cancer |
Verastem, Inc. | November 2013 | Phase 1 |
| NCT02372227 | Terminated | Drug: VS-5584 & VS-6063 | Relapsed Malignant Mesothelioma |
Verastem, Inc. | December 2011 | Phase 1 |
MS-based kinase-binding profile of3 (CZ415)across a set of protein kinases identified from mixed human cell-line lysates (285 kinases identified).
Activity of3in cellular assays: (A) Dose-dependent inhibition of S6RP phosphorylation in HEK293T after 2 h treatment of3, normalized to total S6RP levels. IC50= 14.5 nM (95% CI 11.5 to 18.3 nM,n= 4). (B) Dose-dependent inhibition of Akt phosphorylation in HEK293T after 2 h treatment of3, normalized to total Akt levels.ACS Med Chem Lett.2016 Jun 10;7(8):768-73. |
Time-dependent plasma concentration of3after intravenous bolus (iv, circle) and oral solution (po, square) administration to rats. Rats were dosed at 1 mg/kg (iv,n= 3) or 3 mg/kg (po,n= 3). Vehicle: 5% DMSO/95% (10% Kleptose). Compound3in a mouse CIA model. (A) Clinical arthritis score, all paws (Scored 0–5).ACS Med Chem Lett.2016 Jun 10;7(8):768-73. |
Compound3in anti-CD3 mouse model. (A) pS6RP levels (normalized to total S6RP) measured in spleens of compound treated as compared to disease vehicle group (p< 0.01 for 1 mg/kg of3;p< 0.001 for 3 and 10 mg/kg of3; one outlier removed in normal control and disease vehicle group). (B) Exposure response fit: pS6RP levels at terminal exposure. EC500.22 μM (95% CI 0.15 to 0.32 μM). (C) pAkt levels (normalized to total Akt) measured in spleens of compound treated as compared to disease vehicle group (p< 0.001 for 1, 3, and 10 mg/kg of3). (D) Exposure response fit: pAkt levels at terminal exposure. EC500.055 μM (95% CI 0.048 to 0.065 μM).ACS Med Chem Lett.2016 Jun 10;7(8):768-73. |
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