VS-5584
featured

    WARNING: This product is for research use only, not for human or veterinary use.

MedKoo CAT#: 206109

CAS#: 1246560-33-7

Description: VS-5584, also known as SB2343, is a potent and selective inhibitor of both phosphatidylinositol 3 kinase (PI3K) and mammalian target of rapamycin (mTOR) kinase in the PI3K/mTOR signaling pathway, with potential antineoplastic activity. PI3K/mTOR kinase inhibitor VS-5584 inhibits mTOR kinase and all class I PI3K isoforms. Consequently, this disrupts phosphorylation of substrates downstream of PI3K and mTOR and may result in apoptosis and growth inhibition in susceptible tumor cells. Activation of the PI3K/mTOR pathway promotes cell growth, survival, and resistance to chemotherapy and radiotherapy.


Chemical Structure

img
VS-5584
CAS# 1246560-33-7

Theoretical Analysis

MedKoo Cat#: 206109
Name: VS-5584
CAS#: 1246560-33-7
Chemical Formula: C17H22N8O
Exact Mass: 354.19166
Molecular Weight: 354.41
Elemental Analysis: C, 57.61; H, 6.26; N, 31.62; O, 4.51

Price and Availability

Size Price Availability Quantity
10.0mg USD 150.0 Ready to ship
25.0mg USD 250.0 Ready to ship
50.0mg USD 450.0 Ready to ship
100.0mg USD 650.0 Ready to ship
200.0mg USD 1050.0 Ready to ship
500.0mg USD 1850.0 Ready to ship
1.0g USD 2850.0 2 Weeks
2.0g USD 4250.0 2 weeks
5.0g USD 6950.0 2 weeks
Click to view more sizes and prices
Bulk inquiry

Synonym: VS5584; VS 5584; VS5584; SB2343; SB2343; SB 2343.

IUPAC/Chemical Name: 5-(9-isopropyl-8-methyl-2-morpholino-9H-purin-6-yl)pyrimidin-2-amine

InChi Key: QYBGBLQCOOISAR-UHFFFAOYSA-N

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)

SMILES Code: NC1=NC=C(C2=C3N=C(C)N(C(C)C)C3=NC(N4CCOCC4)=N2)C=N1

Appearance: White to off-white crystalline solid

Purity: >98% (or refer to the Certificate of Analysis)

Shipping Condition: Shipped under ambient temperature as non-hazardous chemical. This product is stable enough for a few weeks during ordinary shipping and time spent in Customs.

Storage Condition: Dry, dark and at 0 - 4 C for short term (days to weeks) or -20 C for long term (months to years).

Solubility: Soluble in DMSO, not in water

Shelf Life: >2 years if stored properly

Drug Formulation: This drug may be formulated in DMSO

Stock Solution Storage: 0 - 4 C for short term (days to weeks), or -20 C for long term (months).

HS Tariff Code: 2934.99.9001

Biological target: 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.
In vitro activity: Western blot analysis confirms the dual inhibitory activity of VS-5584. It showed that the protein levels of the substrates of (1) the PI3K pathway- phospho-Akt (Thr308) and phospho-GSKβ as well as substrate of (2) the mTORC2 pathway phospho-Akt (Ser473) and (3) mTOR/AKT substrate, phospho-S6 have been attenuated by VS-5584 treatment. Expression levels of phosphorylated Akt (Ser473) were completely abolished in H929 (hypersensitive) and reduced in OPM2 (less sensitive) (Figure (Figure1A).1A). Phospho-Akt(Thr308), phospho-GSKβ and Phospho-S6 ribosomal protein expression levels were similarly downregulated, albeit requiring a higher concentration of VS-5584. Additionally this study observes no significant change in the levels of phospho-p44/42-MAPK, thus verifying the specific targeting of VS-5584 on the PI3K/mTOR/Akt signaling pathway. Reference: Oncotarget. 2017 Nov 24; 8(60): 101847–101864. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5731918/
In vivo activity: This study first used MDA-MB-231 triple-negative human breast cancer cells implanted orthotopically in the mouse mammary fat pad. After tumors reached a volume of approximately 200 mm3, VS-5584 was administered orally at 25 mg/kg once daily for 9 days. Tumors were harvested and dissociated into single cells and subjected to CSC assays without further compound treatment (Fig. 3A). Results of the Aldefluor assay showed that the percentage of Aldefluor+ cells was relatively low with an average of 0.7% in control tumors, VS-5584 treatment caused significant reduction of the proportion of Aldefluor+ CSC to 0.2% (P = 0.015, Fig. 3B, Supplementary Fig. S5). A more rigorous and functional test for CSC is the limiting dilution assay. Accordingly, cells dissociated from either VS-5584- or vehicle-treated tumors were injected into immunodeficient mice in limiting dilutions. Cells from VS-5584–treated tumors displayed a 7-fold reduction of TIF, confirming reduction of CSC in tumors by VS-5584 treatment (Fig. 3C). Reference: Cancer Res. 2015 Jan 15;75(2):446-55. https://cancerres.aacrjournals.org/content/75/2/446.long

Solubility Data

Solvent Max Conc. mg/mL Max Conc. mM
Solubility
DMSO 39.78 112.24
DMF 100.0 28.21
DMF:PBS (pH 7.2) (1:1) 0.5 1.41
Ethanol 3.0 8.46

Preparing Stock Solutions

The following data is based on the product molecular weight 354.41 Batch specific molecular weights may vary from batch to batch due to the degree of hydration, which will affect the solvent volumes required to prepare stock solutions.

Recalculate based on batch purity %
Concentration / Solvent Volume / Mass 1 mg 5 mg 10 mg
1 mM 1.15 mL 5.76 mL 11.51 mL
5 mM 0.23 mL 1.15 mL 2.3 mL
10 mM 0.12 mL 0.58 mL 1.15 mL
50 mM 0.02 mL 0.12 mL 0.23 mL
Formulation protocol: 1. Mustafa N, Ting Lee JX, Adina Nee HF, Bi C, Chung TH, Hart S, Chng WJ. VS-5584 mediates potent anti-myeloma activity via the upregulation of a class II tumor suppressor gene, RARRES3 and the activation of Bim. Oncotarget. 2017 Oct 20;8(60):101847-101864. doi: 10.18632/oncotarget.21988. PMID: 29254208; PMCID: PMC5731918. 2. Shao Z, Bao Q, Jiang F, Qian H, Fang Q, Hu X. VS-5584, a Novel PI3K-mTOR Dual Inhibitor, Inhibits Melanoma Cell Growth In Vitro and In Vivo. PLoS One. 2015 Jul 23;10(7):e0132655. doi: 10.1371/journal.pone.0132655. PMID: 26204252; PMCID: PMC4512677. 3. Ning C, Liang M, Liu S, Wang G, Edwards H, Xia Y, Polin L, Dyson G, Taub JW, Mohammad RM, Azmi AS, Zhao L, Ge Y. Targeting ERK enhances the cytotoxic effect of the novel PI3K and mTOR dual inhibitor VS-5584 in preclinical models of pancreatic cancer. Oncotarget. 2017 Jul 4;8(27):44295-44311. doi: 10.18632/oncotarget.17869. PMID: 28574828; PMCID: PMC5546481. 4. Kolev VN, Wright QG, Vidal CM, Ring JE, Shapiro IM, Ricono J, Weaver DT, Padval MV, Pachter JA, Xu Q. PI3K/mTOR dual inhibitor VS-5584 preferentially targets cancer stem cells. Cancer Res. 2015 Jan 15;75(2):446-55. doi: 10.1158/0008-5472.CAN-14-1223. Epub 2014 Nov 28. PMID: 25432176.
In vitro protocol: 1. Mustafa N, Ting Lee JX, Adina Nee HF, Bi C, Chung TH, Hart S, Chng WJ. VS-5584 mediates potent anti-myeloma activity via the upregulation of a class II tumor suppressor gene, RARRES3 and the activation of Bim. Oncotarget. 2017 Oct 20;8(60):101847-101864. doi: 10.18632/oncotarget.21988. PMID: 29254208; PMCID: PMC5731918. 2. Shao Z, Bao Q, Jiang F, Qian H, Fang Q, Hu X. VS-5584, a Novel PI3K-mTOR Dual Inhibitor, Inhibits Melanoma Cell Growth In Vitro and In Vivo. PLoS One. 2015 Jul 23;10(7):e0132655. doi: 10.1371/journal.pone.0132655. PMID: 26204252; PMCID: PMC4512677.
In vivo protocol: 1. Ning C, Liang M, Liu S, Wang G, Edwards H, Xia Y, Polin L, Dyson G, Taub JW, Mohammad RM, Azmi AS, Zhao L, Ge Y. Targeting ERK enhances the cytotoxic effect of the novel PI3K and mTOR dual inhibitor VS-5584 in preclinical models of pancreatic cancer. Oncotarget. 2017 Jul 4;8(27):44295-44311. doi: 10.18632/oncotarget.17869. PMID: 28574828; PMCID: PMC5546481. 2. Kolev VN, Wright QG, Vidal CM, Ring JE, Shapiro IM, Ricono J, Weaver DT, Padval MV, Pachter JA, Xu Q. PI3K/mTOR dual inhibitor VS-5584 preferentially targets cancer stem cells. Cancer Res. 2015 Jan 15;75(2):446-55. doi: 10.1158/0008-5472.CAN-14-1223. Epub 2014 Nov 28. PMID: 25432176.

Molarity Calculator

Calculate the mass, volume, or concentration required for a solution.
=
x
x
g/mol

*When preparing stock solutions always use the batch-specific molecular weight of the product found on the vial label and SDS / CoA (available online).

Reconstitution Calculator

The reconstitution calculator allows you to quickly calculate the volume of a reagent to reconstitute your vial. Simply enter the mass of reagent and the target concentration and the calculator will determine the rest.

=
÷

Dilution Calculator

Calculate the dilution required to prepare a stock solution.
x
=
x

1: Shao Z, Bao Q, Jiang F, Qian H, Fang Q, Hu X. VS-5584, a Novel PI3K-mTOR Dual Inhibitor, Inhibits Melanoma Cell Growth In Vitro and In Vivo. PLoS One. 2015 Jul 23;10(7):e0132655. doi: 10.1371/journal.pone.0132655. eCollection 2015. PubMed PMID: 26204252; PubMed Central PMCID: PMC4512677.

2: Kolev VN, Wright QG, Vidal CM, Ring JE, Shapiro IM, Ricono J, Weaver DT, Padval MV, Pachter JA, Xu Q. PI3K/mTOR dual inhibitor VS-5584 preferentially targets cancer stem cells. Cancer Res. 2015 Jan 15;75(2):446-55. doi: 10.1158/0008-5472.CAN-14-1223. Epub 2014 Nov 28. PubMed PMID: 25432176.

3: Poulsen A, Nagaraj H, Lee A, Blanchard S, Soh CK, Chen D, Wang H, Hart S, Goh KC, Dymock B, Williams M. Structure and ligand-based design of mTOR and PI3-kinase inhibitors leading to the clinical candidates VS-5584 (SB2343) and SB2602. J Chem Inf Model. 2014 Nov 24;54(11):3238-50. doi: 10.1021/ci500493m. Epub 2014 Oct 23. PubMed PMID: 25317974.

4: 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. PubMed PMID: 23270925; PubMed Central PMCID: PMC3588144.

VS-5584

10.0mg / USD 150.0


Additional Information

   VS-5584 is a selective dual pan-PI3K/mTOR inhibitor being developed by Verastem. Research has shown that VS-5584 has equivalent potency against mTOR (IC(50) = 37 nmol/L) and all class I phosphoinositide 3-kinase (PI3K) isoforms IC(50): PI3Kα = 16 nmol/L; PI3Kβ = 68 nmol/L; PI3Kγ = 25 nmol/L; PI3Kδ = 42 nmol/L, without relevant activity on 400 lipid and protein kinases. VS-5584 shows robust modulation of cellular PI3K/mTOR pathways, inhibiting phosphorylation of substrates downstream of PI3K and mTORC1/2. VS-5584 exhibits favorable pharmacokinetic properties after oral dosing in mice and is well tolerated. VS-5584 induces long-lasting and dose-dependent inhibition of PI3K/mTOR signaling in tumor tissue, leading to tumor growth inhibition in various rapalog-sensitive and -resistant human xenograft models. Furthermore, VS-5584 is synergistic with an EGF receptor inhibitor in a gastric tumor model. The unique selectivity profile and favorable pharmacologic and pharmaceutical properties of VS-5584 and its efficacy in a wide range of human tumor models supports further investigations of VS-5584 in clinical trials.