VS-5584 (SB2343)

Catalog No.S7016

VS-5584 (SB2343) is a potent and selective dual PI3K/mTOR inhibitor for mTOR, PI3Kα/β/δ/γ with IC50 of 3.4 nM and 2.6-21 nM, respectively. Phase 1.

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VS-5584 (SB2343) Chemical Structure

VS-5584 (SB2343) Chemical Structure
Molecular Weight: 354.41

Validation & Quality Control

Quality Control & MSDS

Product Information

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  • Research Area
  • Inhibition Profile

Product Description

Biological Activity

Description VS-5584 (SB2343) is a potent and selective dual PI3K/mTOR inhibitor for mTOR, PI3Kα/β/δ/γ with IC50 of 3.4 nM and 2.6-21 nM, respectively. Phase 1.
Targets PI3Kα [1] PI3Kδ [1] PI3Kγ [1] mTOR [1] PI3Kβ [1]
IC50 2.6 nM 2.7 nM 3.0 nM 3.4 nM 21 nM
In 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. 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. [1] 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. [2]
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. [1] 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). [2]
Features

Protocol(Only for Reference)

Kinase Assay: [2]

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 MgCl 2, 3 mM MnCl 2, 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 is incubated for 60 min 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 1X LANCE® Detection Buffer is then added and incubated for 60 min.

Cell Assay: [2]

Cell lines SNU-478, SNU-1196, SNU-245, SNU-1079, SNU-308, and SNU-869
Concentrations ~10 μM
Incubation Time 48 h
Method CellTiter-Glo assay

Animal Study: [2]

Animal Models Male (PC3 and COLO 205) or female (MV4-11 and HuH7) BALB/c nude mice or female SCID mice (NCI-N87)
Formulation 0.5% methylcellulose (w/v) and 0.1% Tween-80 in H2O (MC/Tween)
Dosages 11 mg/kg, 25 mg/kg once daily
Administration orally

Conversion of different model animals based on BSA (Value based on data from FDA Draft Guidelines)

SpeciesMouseRatRabbitGuinea pigHamsterDog
Weight (kg)0.020.151.80.40.0810
Body Surface Area (m2)0.0070.0250.150.050.020.5
Km factor36128520
Animal A (mg/kg) = Animal B (mg/kg) multiplied by  Animal B Km
Animal A Km

For example, to modify the dose of resveratrol used for a mouse (22.4 mg/kg) to a dose based on the BSA for a rat, multiply 22.4 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for resveratrol of 11.2 mg/kg.

Rat dose (mg/kg) = mouse dose (22.4 mg/kg) ×  mouse Km(3)  = 11.2 mg/kg
rat Km(6)
1

References

[1] JA Pachter, et al. Molecular Targets and Cancer Therapeutics, 2012, abstract 405.

[2] Hart S, et al. Mol Cancer Ther, 2013, 12(2), 151-161.

Clinical Trial Information( data from http://clinicaltrials.gov, updated on 2016-06-25)

NCT Number Recruitment Conditions Sponsor
/Collaborators
Start Date Phases
NCT02372227 Active, not recruiting Relapsed Malignant Mesothelioma Verastem, Inc. January 2015 Phase 1
NCT01991938 Recruiting Non Hematologic Cancers|Metastatic Cancer|Lymphoma Verastem, Inc. November 2013 Phase 1

Chemical Information

Molecular Weight (MW) 354.41
Formula

C17H22N8O

CAS No. 1246560-33-7
Storage 3 years -20℃powder
6 months-80℃in solvent
Synonyms N/A
Solubility (25°C) * In vitro DMSO 71 mg/mL (200.33 mM)
Ethanol 3 mg/mL (8.46 mM)
Water <1 mg/mL (<1 mM)
In vivo 0.5% methylcellulose+0.2% Tween 80 30 mg/mL
* <1 mg/ml means slightly soluble or insoluble.
* Please note that Selleck tests the solubility of all compounds in-house, and the actual solubility may differ slightly from published values. This is normal and is due to slight batch-to-batch variations.
Chemical Name 2-Pyrimidinamine, 5-[8-methyl-9-(1-methylethyl)-2-(4-morpholinyl)-9H-purin-6-yl]-

Tech Support

Answers to questions you may have can be found in the inhibitor handling instructions. Topics include how to prepare stock solutions, how to store inhibitors, and issues that need special attention for cell-based assays and animal experiments.

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