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CAS No. 1246560-33-7
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.
Selleck's VS-5584 (SB2343) has been cited by 11 publications
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Effect of VS-5584 on platelet adhesion. A-F: WP (A, B) and PRP (D, E) were treated with DMSO as vehicle (A, D; n = 3) or with 20 nM (B; n = 3) and 20 μM (E; n = 3) of VS-5584 and seeded on siliconized coverslips for the quantitative analysis of WP (C) and PRP adhesion (F). Scale bars: A, B, D, E = 50 μm; Data are given in % of vehicle. Mean ± SEM. *p < 0.05 vs. vehicle. G, H: Representative images of WP treated with vehicle (G) or 20 nM of VS-5584 (H). The number of non-spread cells (arrows) is higher in VS-5584-treated WP. Scale bars: 20 μm. I: Quantification of spread platelets based on their morphology. Data are given in % of vehicle. Mean ± SEM. *p < 0.05 vs. vehicle.
Platelets, 2017, 29(3):277-287. VS-5584 (SB2343) purchased from Selleck.
Effects of either VS-5584 or ATO alone and their combination on inhibition of PI3K/Akt/mTOR pathway. (A) Western blot analysis for phosphorylation levels of two downstream components of the PI3K/Akt/ mTOR network. NALM-6 cells were treated with 10 μM VS-5584 or 0.2 μM ATO alone and their co-treatment for 60 h. Cell-lysates were prepared, SDS–PAGE and western blot analysis were carried out using p-IκBα and p-S6 specific Abs. Actin serves as loading control. One representative of three independent experiments is shown. (B) qRTPCR analysis for evaluation the effects of VS-5584 and ATO and their combination on expression of Akt downstream target genes. NALM-6 cells were treated with 10 μM VS-5584 and 0.2 μM ATO alone and in combination for 60 h. RNA extraction and cDNA synthesis were carried out, expression of indicated genes measured using quantitative RT–PCR and normalized to the expression of β-actin mRNA. The results are expressed as mean ± SD of at least three independent experiments (*p < 0.05, **p < 0.01, ***p < 0.001. p values in single agent treatment groups are calculated compared to control and in combined group compared to ATO).
Biomed Pharmacother, 2018, 428-437. VS-5584 (SB2343) purchased from Selleck.
VS-5584 inhibits melanoma cell survival and proliferation-Established melanoma cell lines (A375, A-2058 and SK-MEL-3), patient-derived primary melanoma cells, B10BR melanocytes and primary human keratinocytes (“Kera”) were treated with applied concentration of VS-5585 (“VS”) or vehicle control (“C”, 0.1% of DMSO), cell survival was tested by MTT assay (A, E and F) and trypan blue exclusion assay (B, for A375 cells); Cell proliferation was analyzed by through [H3] Thymidine incorporation assay (C, for A375 cells) and clonogenicity assay (D, for A375 cells). Data were expressed as mean ± SD, experiments were repeated three times. *p<0.05 vs group “C”.
PLoS One, 2015, 10(7):e0132655.. VS-5584 (SB2343) purchased from Selleck.
Effect of VS-5584 on platelet viability. A, B: WP (A) and PRP (B) were incubated with different concentrations of VS-5584 (black bars, n = 4) or DMSO as vehicle (white bars, n = 4) for 30 min. Untreated WP or PRP served as negative control (grey bars, n = 4). Platelet viability was assessed by flow cytometric detection of calcein/CD42b-staining. Data are given in % of vehicle. Mean ± SEM. *p < 0.05 vs. vehicle; § p < 0.05 vs. 5 and 10 nM or µM VS-5584; °p < 0.05 vs. 5, 10 and 20 nM or µM VS-5584; $ p < 0.05 vs. 5, 10, 20 and 50 nM or µM VS-5584; +p < 0.05 vs. 5, 10, 20, 50 and 200 nM or µM VS-5584. C, D: WP (C) and PRP (D) were incubated with different concentrations of VS-5584 (black bars, n = 3) or DMSO as vehicle (white bars, n = 3) for 30 min. Untreated WP or PRP served as negative control (grey bars, n = 3) and PAR-1-AP-activated platelets served as positive control (crosshatched bars,n=3). Platelet viability was assessed by flow cytometric detection of annexin staining. Data are given in % of vehicle. Mean ± SEM. *p < 0.05 vs. vehicle; °p < 0.05 vs. 5, 10 and 20 nM or µM VS-5584; $ p < 0.05 vs. 5, 10, 20 and 50 nM or µM VS-5584; ~p < 0.05 vs. 5, 10, 20, 50, 200 and 500 nM or µM VS-5584.
Platelets, 2018, 29(3):277-287. VS-5584 (SB2343) purchased from Selleck.
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Choose Selective PI3K Inhibitors
|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.|
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.  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. 
|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.  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). |
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.
|In vitro||DMSO||71 mg/mL (200.33 mM)|
|Ethanol||3 mg/mL (8.46 mM)|
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0.5% methylcellulose+0.2% Tween 80
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Clinical Trial Information
|NCT Number||Recruitment||interventions||Conditions||Sponsor/Collaborators||Start Date||Phases|
|NCT02372227||Terminated||Drug: VS-5584 and VS-6063||Relapsed Malignant Mesothelioma||Verastem Inc.||January 2015||Phase 1|
|NCT01991938||Terminated||Drug: VS-5584||Non Hematologic Cancers|Metastatic Cancer|Lymphoma||Verastem Inc.||November 2013||Phase 1|
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