VS-5584 | SB2343 | CAS#1246560-33-7 | PI3K/mTOR Kinase Inhibitor

MedKoo Cat#: 206109 | Name: VS-5584

Description:

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

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

VS-5584

CAS#1246560-33-7 (VS-5584)

Theoretical Analysis

MedKoo Cat#: 206109

Name: VS-5584

CAS#: 1246560-33-7 (VS-5584)

Chemical Formula: C17H22N8O

Exact Mass: 354.1917

Molecular Weight: 354.41

Elemental Analysis: C, 57.61; H, 6.26; N, 31.62; O, 4.51

Price and Availability

Size	Price	Availability
10mg	USD 150.00	Ready to ship
25mg	USD 250.00	Ready to ship
50mg	USD 450.00	Ready to ship
100mg	USD 650.00	Ready to ship
200mg	USD 1,050.00	Ready to ship
500mg	USD 1,850.00	Ready to ship
1g	USD 2,850.00	2 Weeks
2g	USD 4,250.00	2 weeks

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Related CAS #

1246535-95-4 (VS-5584 analog) 1246560-33-7 (VS-5584)

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

More Info

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.

Product Data

Product Data

Certificate of Analysis

View CoA: current batch, Lot#B8B04C12

QC Data

View QC data: current batch, Lot#B8B04C12

Safety Data Sheet (SDS)

View Safety Data Sheet (SDS)

Instruction

View handling instruction

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

	Solvent	mg/mL	mM
Solubility
	DMSO	39.8	112.24
	DMF	100.0	28.21
	DMF:PBS (pH 7.2) (1:1)	0.5	1.41
	Ethanol	3.0	8.46

Note: There can be variations in solubility for the same chemical from different vendors or different batches from the same vendor. The following factors can affect the solubility of the same chemical: solvent used for crystallization, residual solvent content, polymorphism, salt versus free form, degree of hydration, solvent temperature. Please use the solubility data as a reference only. Warming and sonication will facilitate dissolving. Still have questions? Please contact our Technical Support scientists.

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.

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:

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.

1: Ozel B, Kipcak S, Caglar HO, Kayabasi C, Goker Bagca B, Gunduz C, Selvi Gunel N, Biray Avci C. PI3K/mTOR Inhibitor VS-5584 Alters Expression of WNT Signaling Genes and Induces Apoptosis in Lung Adenocarcinoma Cells: In Vitro and In Silico Insight. Cell Biochem Biophys. 2024 Dec 17. doi: 10.1007/s12013-024-01643-9. Epub ahead of print. PMID: 39690396. 2: Grand-Guillaume J, Mansi R, Gaonkar RH, Zanger S, Fani M, Eugster PJ, Beck Popovic M, Grouzmann E, Abid K. CUDC-907, a dual PI3K/histone deacetylase inhibitor, increases meta-iodobenzylguanidine uptake (123/131I-mIBG) in vitro and in vivo: a promising candidate for advancing theranostics in neuroendocrine tumors. J Transl Med. 2023 Sep 7;21(1):604. doi: 10.1186/s12967-023-04466-z. PMID: 37679770; PMCID: PMC10485979. 3: Luo Y, Zhao H, Zhu J, Zhang L, Zha J, Zhang L, Ding Y, Jian X, Xia J, Xu B, Qi Z. SIRT2 inhibitor SirReal2 enhances anti-tumor effects of PI3K/mTOR inhibitor VS-5584 on acute myeloid leukemia cells. Cancer Med. 2023 Sep;12(18):18901-18917. doi: 10.1002/cam4.6480. Epub 2023 Sep 1. PMID: 37658623; PMCID: PMC10557894. 4: Zhao S, Li Y, Li G, Ye J, Wang R, Zhang X, Li F, Gao C, Li J, Jiang J, Mi Y. PI3K/mTOR inhibitor VS-5584 combined with PLK1 inhibitor exhibits synergistic anti-cancer effects on non-small cell lung cancer. Eur J Pharmacol. 2023 Oct 15;957:176004. doi: 10.1016/j.ejphar.2023.176004. Epub 2023 Aug 23. PMID: 37625683. 5: Kayabasi C, Gunduz C. The lncRNA expression profile signature of leukemia stem cells is altered upon PI3K/mTOR inhibition: an in vitro and in silico study. Nucleosides Nucleotides Nucleic Acids. 2024;43(2):99-115. doi: 10.1080/15257770.2023.2236143. Epub 2023 Jul 20. PMID: 37470414. 6: Liu JF, Su G, Chen LX, Zhou JP, Gao J, Zhang JJ, Wu QH, Chen W, Chen DY, Zhang ZC. Irisin Attenuates Apoptosis Following Ischemia-Reperfusion Injury Through Improved Mitochondria Dynamics and ROS Suppression Mediated Through the PI3K/Akt/mTOR Axis. Mol Neurobiol. 2023 Aug;60(8):4261-4272. doi: 10.1007/s12035-023-03336-5. Epub 2023 Apr 15. PMID: 37060502. 7: Kayabasi C, Yelken BO, Asik A, Okcanoglu TB, Sogutlu F, Gasimli R, Susluer SY, Saydam G, Avci CB, Gunduz C. PI3K/mTOR dual-inhibition with VS-5584 enhances anti-leukemic efficacy of ponatinib in blasts and Ph-negative LSCs of chronic myeloid leukemia. Eur J Pharmacol. 2021 Nov 5;910:174446. doi: 10.1016/j.ejphar.2021.174446. Epub 2021 Aug 27. PMID: 34461124. 8: Liu S, Zhao S, Dong Y, Wang T, Niu X, Zhao L, Wang G. Antitumor activity and mechanism of resistance of the novel HDAC and PI3K dual inhibitor CUDC-907 in pancreatic cancer. Cancer Chemother Pharmacol. 2021 Mar;87(3):415-423. doi: 10.1007/s00280-020-04210-0. Epub 2021 Jan 3. PMID: 33392641. 9: Zhou C, Li X, He A, Liu T, Tian J, Jiang M, Fang L. Development of a UPLC- MS/MS Method for the Quantification of VS-5584 and Its Application in Pharmacokinetic Studies in Rats. J Anal Methods Chem. 2020 Dec 16;2020:8811522. doi: 10.1155/2020/8811522. PMID: 33381351; PMCID: PMC7759402. 10: Chen Y, Tsai HW, Tsai YH, Tseng SH. VS-5584, a PI3K/mTOR dual inhibitor, exerts antitumor effects on neuroblastomas in vitro and in vivo. J Pediatr Surg. 2021 Aug;56(8):1441-1448. doi: 10.1016/j.jpedsurg.2020.10.033. Epub 2020 Nov 5. PMID: 33189297. 11: Bharadwaj S, Azhar EI, Kamal MA, Bajrai LH, Dubey A, Jha K, Yadava U, Kang SG, Dwivedi VD. SARS-CoV-2 Mpro inhibitors: identification of anti- SARS-CoV-2 Mpro compounds from FDA approved drugs. J Biomol Struct Dyn. 2022 Apr;40(6):2769-2784. doi: 10.1080/07391102.2020.1842807. Epub 2020 Nov 5. PMID: 33150855; PMCID: PMC7651494. 12: Xu M, Xu L, Wang Y, Dai G, Xue B, Liu YY, Zhu J, Zhu J. BRD4 inhibition sensitizes renal cell carcinoma cells to the PI3K/mTOR dual inhibitor VS-5584. Aging (Albany NY). 2020 Oct 13;12(19):19147-19158. doi: 10.18632/aging.103723. Epub 2020 Oct 13. PMID: 33051401; PMCID: PMC7732329. 13: Sun JY, Hou YJ, Yin YB, Wang FZ, Yang MF, Zhang YY, Fan CD, Sun BL. CCT128930 induces G1-phase arrest and apoptosis and synergistically enhances the anticancer efficiency of VS5584 in human osteosarcoma cells. Biomed Pharmacother. 2020 Oct;130:110544. doi: 10.1016/j.biopha.2020.110544. Epub 2020 Jul 25. Erratum in: Biomed Pharmacother. 2020 Dec;132:110931. doi: 10.1016/j.biopha.2020.110931. PMID: 32721630. 14: Sun JY, Hou YJ, Cui HJ, Zhang C, Yang MF, Wang FZ, Sun Z, Fan CD, Sun BL, Oh JR. VS-5584 Inhibits Human Osteosarcoma Cells Growth by Induction of G1- phase Arrest through Regulating PI3K/mTOR and MAPK Pathways. Curr Cancer Drug Targets. 2020;20(8):616-623. doi: 10.2174/1568009620666200414150353. PMID: 32286946. 15: Mukhopadhyay A, Drew Y, Matheson E, Salehan M, Gentles L, Pachter JA, Curtin NJ. Evaluating the potential of kinase inhibitors to suppress DNA repair and sensitise ovarian cancer cells to PARP inhibitors. Biochem Pharmacol. 2019 Sep;167:125-132. doi: 10.1016/j.bcp.2018.10.011. Epub 2018 Oct 17. PMID: 30342021. 16: Toosi B, Zaker F, Alikarami F, Kazemi A, Teremmahi Ardestanii M. VS-5584 as a PI3K/mTOR inhibitor enhances apoptotic effects of subtoxic dose arsenic trioxide via inhibition of NF-κB activity in B cell precursor-acute lymphoblastic leukemia. Biomed Pharmacother. 2018 Jun;102:428-437. doi: 10.1016/j.biopha.2018.03.009. Epub 2018 Mar 23. PMID: 29574283. 17: Zhou J, Toh SH, Chan ZL, Quah JY, Chooi JY, Tan TZ, Chong PSY, Zeng Q, Chng WJ. A loss-of-function genetic screening reveals synergistic targeting of AKT/mTOR and WTN/β-catenin pathways for treatment of AML with high PRL-3 phosphatase. J Hematol Oncol. 2018 Mar 7;11(1):36. doi: 10.1186/s13045-018-0581-9. PMID: 29514683; PMCID: PMC5842526. 18: 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. 19: Su Y, Li X, Ma J, Zhao J, Liu S, Wang G, Edwards H, Taub JW, Lin H, Ge Y. Targeting PI3K, mTOR, ERK, and Bcl-2 signaling network shows superior antileukemic activity against AML ex vivo. Biochem Pharmacol. 2018 Feb;148:13-26. doi: 10.1016/j.bcp.2017.11.022. Epub 2017 Dec 5. PMID: 29208365; PMCID: PMC6858997. 20: 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.