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VS-5584

MCE China：VS-5584

Brand：MedChemExpress (MCE)

Cat. No.HY-16585

CAS：1246560-33-7

Synonyms：SB2343

Purity：99.14%

Storage：Powder -20°C 3 years 4°C 2 years In solvent -80°C 2 years -20°C 1 year

Shipping：Room temperature in continental US; may vary elsewhere.

Description：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. VS-5584 simultaneously blocks mTORC2 as well as mTORC1.

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 (0.001, 0.01, 0.1,1,10 and 100 μM) preferentially inhibits cancer stem cells in HMLE breast cancer cells while Paclitaxel increases the percentage of cancer stem cells. VS-5584 (0.1, 1, 10, 100 and 1000 nM) reduces the number of Aldefluor-positive cancer stem cells while Paclitaxel increases the percentage of cancer stem cells. VS-5584 (10, 30, 100, 300 nM) reduces the percentage of cancer stem cells (side population) in a Hoechst dye exclusion assay[1]. VS-5584 is a potent inhibitor of mTOR (IC50=37 nM) as well as class I PI3K isoforms (IC50: PI3Kα=16 nM; PI3Kβ=68 nM; PI3Kγ=25 nM; PI3Kδ=42 nM). All other evaluated kinases show negligible binding when tested up to 10 μM VS-5584[1].

In Vivo：Nude mice bearing MDA-MB-231 human breast cancer tumors are treated for 5 days with once daily oral VS-5584 (25 mg/kg). Oral treatment of tumor bearing mice with VS-5584 reduces cancer atem cells analyzed from extracted tumors. Mice are implanted with tumor fragments from a docetaxel-resistant patient-derived triple negative breast cancer. Mice are treated with VS-5584 (20 mg/kg, po, qd) or Docetaxel (20 mg/kg, i.v.). Oral VS-5584 induces tumor regression in a Docetaxel-resistant patient-derived breast cancer model[1]. A single oral dose of VS-5584 is rapidly absorbed with a tmax of 0.9 hours and an elimination half-life of 10 hours. To determine the pharmacokinetic and pharmacodynamic relationship in tumors, PC3-tumor–bearing mice are treated with a single dose of VS-5584 and plasma and tumors are harvested after 6 hours and analyzed for concentrations of VS-5584 and effects on target efficacy biomarkers. Plasma levels of VS-5584 increase dose-dependently. For evaluation of efficacy in a Rapamycin-sensitive PC3 engraftment model, tumor-bearing mice are treated with VS-5584 for 28 days in comparison with the rapalog Everolimus. VS-5584 is well tolerated at both doses tested (11 and 25 mg/kg) with minimal weight loss (mean 4.7% on day 27). Treatment with VS-5584 leads to significant tumor growth inhibition (TGI) of 79% and 113% for 11 and 25 mg/kg, respectively[1].

Animal Administration：Mice[1]Athymic BALB/c nude mice (BALB/cOlaHsd-Foxn1nu) are used. Fox-Chase severe combined immunodeficient (SCID) mice (CB17/Icr-Prkdcscid/CrlBltw) are used. Male (PC3 and COLO 205) or female (MV4-11 and HuH7) BALB/c nude mice or female SCID mice (NCI-N87) are implanted intradermally in the right flank with 5×106 (PC3, COLO205, HuH7, NCI-N87) or 1×107 (MV4-11) cells. Cells are resuspended in 70% (v/v; COLO205 and HuH7 only) or 50% (v/v) serum-free growth medium/Matrigel and injected in a total volume of 100 μL, using a 27.5-gauge needle. Dosing started 7 to 14 days after tumor implantation. VS-5584 (11 and 25 mg/kg) is dosed daily orally[1].

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. Cells are seeded at 30% to 50% confluency for adherent cells, or 2,000 to 6,000 cells for suspension cells and treated the following day with VS-5584 (in triplicates) at concentrations up to 10 μM for 48 hours. Cell viability is monitored using the CellTiter-Glo assay. Dose-response curves were plotted to determine IC50 values for the compounds using the XL-fit software[1].

IC50 & Target：PI3Kα 16 nM (IC50) PI3Kγ 25 nM (IC50) PI3Kδ 42 nM (IC50) PI3Kβ 68 nM (IC50) Vps34 7470 nM (IC50) mTOR 37 nM (IC50) mTORC1 mTORC2 DNA-PK 1270 nM (IC50)

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References：

[1]. Hart S, et al. VS-5584, a novel and highly selective PI3K/mTOR kinase inhibitor for the treatment of cancer. Mol Cancer Ther, 2013, 12(2), 151-161.  [Content Brief]