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Research Area
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Description
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Cancer |
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Biological Activity
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Description
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NVP-AUY922 (VER-52296) is a highly potent HSP90 inhibitor for HSP90α and HSP90β with IC50 of 13 nM and 21 nM, respectively. |
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Targets
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HSP90α |
HSP90β |
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IC50 |
13 nM |
21 nM [1] |
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In Vitro
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NVP-AUY922 inhibits proliferation of various human cancer cell lines in vitro, with an average GI50 of 9 nM. [1] The IC50 values of NVP-AUY922 fall in the range of 2 to 40 nM in these gastric cancer cell lines. IC50 value for the BEAS-2B cells is 28.49 nM. Treatment with NVP-AUY922 does not influence the expression of HSP90, but expression of HSP70 gets elevated by NVP-AUY922 treatment. NVP-AUY922 increases the binding of HSP70 to HSP90. NVP-AUY922 causes p23 dissociation from the HSP90 complex and can then recruit HSP70 to the HSP90 complex.[1] After the treatment with NVP-AUY922, expression of receptor tyrosine kinases including VEGFR1, 2, 3 and PDGFRɑ is decreased. A decrease is also noticed in the expression of Akt and phospho-Akt. Meanwhile, treatment with NVP-AUY922 causes decreased expression of HER-2 in NCI-N87 cells. NVP-AUY922 treatment results in binding of HSP90 to client proteins and setting them up as targets for degradation by the proteasome. NVP-AUY922 can influence cell growth by affecting mutiple signaling pathways. In addition, treatment with the proteasome inhibitor, MG132, restores expression of thymidylate synthase, which is decreased by NVP-AUY922. NVP-AUY922 increases the expression of cleaved caspase-3 leading to apoptosis in HSC-2 cells.[1] |
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In Vivo
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Treatment with NVP-AUY922 causes a robust antitumor response and inhibits p-Akt and VEGF expression in an HSC-2 xenograft model. [2] Regressions are observed in 5 of 12 tumors. Body weight loss is <5% and="" clear="" biomarker="" changes="" consistent="" with="" hsp90="" inhibition="" are="" obtained="" in="" both="" studies="" (supplementary="" fig.="" s5c="" and="" d).="" in="" bt474,="" complete="" loss="" of="" erbb2="" and="" substantial="" depletion="" of="" erα="" are="" shown,="" in="" addition="" to="" reductions="" in="" cdk4="" and="" phospho-erk1/2.="">[3] |
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Clinical Trials
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Features
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Protocol
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Kinase Assay
[3]
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| Kinase assay |
NVP-AUY922 is dissolved in DMSO at a concentration of 10 mM. NVP-AUY922 is assessed against HSP90α, HSP90β, GRP94, TRAP-1, HSP72, and topoisomerase II. Profiling against a panel of kinases has been carried out and screening against a panel of additional enzymes and receptors is performed at Cerep. |
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Cell Assay
[1]
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| Cell Lines |
Human gastric cancer cells NCI-N87 |
| Concentrations |
1 μM |
| Incubation Time |
3 days |
| Methods |
Human gastric cancer cells NCI-N87 (5-7 ×103 in 50 μL/well) are seeded in 96-well plates and incubated at 37 °C for 24 hours, followed by NVP-AUY922 treatment for 1-3 days at 37 °C. After treatment, the cells are assayed by MTT method and analyzed by microplate reader. |
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Animal Study
[3]
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| Animal Models |
Female NCr athymic mice bearing WM266.4 human melanoma xenografts |
| Formulation |
In DMSO and diluted in sterile saline/Tween 20 |
| Doses |
50 mg/kg |
| Administration |
Administered via i.v. or i.p. |
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References |
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[1] Lee KH, et al. Cancer Sci, 2011, 102(7), 1388-1395.
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[2] Okui T, et al. Anticancer Res, 2011, 31(4), 1197-1204.
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[3] Eccles SA, et al. Cancer Res, 2008, 68(8), 2850-2860.
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