Tozasertib (VX-680, MK-0457) is a small-molecule Aurora kinase inhibitor. The Aurora kinases are essential for the regulation of chromosome segregation and cytokinesis during mitosis. Tozasertib (VX-680) blocks cell-cycle progression and induces apoptosis in a diverse range of human tumor types. Tozasertib (VX-680) effectively inhibits proliferation of several different cell lines of clear cell renal carcinoma (IC50s < 10 μM) and blocks the growth of tumors in a rodent model of cancer (80 mg/kg), inhibiting H3 histone phosphorylation, to an increase of apoptotic cells, and to morphological changes such as vacuolization and swelling of the cells and nuclei. The combination of VX-680 and histone deacetylase inhibitor SAHA had a synergistic effect on the proliferation of HUH6 cells. Tozasertib (VX-680) might improve treatment results in HB with increased Aurora kinase activity by inhibiting cell proliferation and induction of apoptosis.
J Hematol Oncol. 2017 Jun 8;10(1):115.
SIX3, a tumor suppressor, inhibits astrocytoma tumorigenesis by transcriptional repression of AURKA/B
Tozasertib purchased from AbMole
|Source||Journal of Hematology & Oncology (2017). Figure 7. VX680 (Abmole Bioscience)|
|Cell Lines||U251, U87 and U118 cell lines|
|Incubation Time||48 and 72 h|
|Results||We found that the U251-SIX3 cells showed less sensitivity to VX680 compared with the U251-CON cells (Fig. 7a). With increased expression of AURKA or AURKB and reduced expression of SIX3, the p53 mutant U251 cells were more sensitive to VX680 treatment, compared with the p53 wild-type U87 cells (Fig. 7b).|
|Cell lines||SW620, K562, HL-60, MIA PaCa-2 and HCT116 cells|
|Preparation method||Analysis of cell proliferation and viability.
Tumor cells were seeded in 96-well plates and incubated with VX-680 for 96 h. To measure DNA synthesis, 0.5 mCi of [3H]thymidine was added to each well 3 h before the end of the experiment. Cells were then collected, and the incorporated radioactivity was counted on a Wallac microplate beta-counter. Cell viability was assessed using Promega CellTiter 96AQ to measure MTS (3-(4,5 dimethylthiazol-2-yl)-5-(3- carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium, inner salt) conversion.
|Incubation time||96 h|
|Animal models||female athymic NCr-nu mice HL-60, MIA PaCa-2 and HCT116 cells tumour xenograft model|
|Formulation||50% PEG 300 in 50 mM phosphate buffer|
|Dosages||q.4.d. at a dose of 12.5, 25, 50 and 75 mg/kg|
|Body Surface Area (m2)||0.007||0.025||0.15||0.05||0.02||0.5|
|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.
|Solubility||DMSO 90 mg/mL|
In vitro evaluation of the Aurora kinase inhibitor VX-680 for Hepatoblastoma.
Dewerth A, et al. Pediatr Surg Int. 2012 Jun;28(6):579-89. PMID: 22526548.
Activity of the Aurora kinase inhibitor VX-680 against Bcr/Abl-positive acute lymphoblastic leukemias.
Fei F, et al. Mol Cancer Ther. 2010 May;9(5):1318-27. PMID: 20388735.
VX-680, a potent and selective small-molecule inhibitor of the Aurora kinases, suppresses tumor growth in vivo.
Harrington EA, et al. Nat Med. 2004 Mar;10(3):262-7. PMID: 14981513.
|Related Aurora Kinase Products|
SNS-314 is a potent and selective inhibitor of Aurora A, Aurora B and Aurora C with IC50 of 9 nM, 31 nM, and 3 nM, respectively.
GSK1070916 is a reversible and ATP-competitive inhibitor of Aurora B/C with IC50 of 3.5 nM/6.5 nM. It displays >100-fold selectivity against the closely related Aurora A-TPX2 complex.
PHA-680632 is potent inhibitor of Aurora A, Aurora B and Aurora C with IC50 of 27 nM, 135 nM and 120 nM, respectively. It has 10- to 200-fold higher IC50 for FGFR1, FLT3, LCK, PLK1, STLK2, and VEGFR2/3.
MK-5108 (VX-689) is a highly selective Aurora A inhibitor with IC50 of 0.064 nM and is 220- and 190-fold more selective for Aurora A than Aurora B/C, while it inhibits TrkA with less than 100-fold selectivity.
PF-03814735 is a novel, potent and reversible inhibitor of Aurora A/B with IC50of 0.8 nM/5 nM, is less potent to Flt3, FAK, TrkA, and minimally active to Met and FGFR1.
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