AUY922 (NVP-AUY922) is a small molecule Heat Shock Protein 90 (HSP90) inhibitor with IC50 values of 13 and 21 nM for HSP90α and HSP90β respectively. AUY922 (NVP-AUY922) potently inhibits HSP90 (Kd = 1.7 nmol/L) and proliferation of human tumor cells with GI50 values of approximately 2 to 40 nmol/L, inducing G1-G2 arrest and apoptosis. AUY922 (NVP-AUY922) inhibited proliferation, chemomigration, and tubular differentiation of human endothelial cells and antiangiogenic activity was reflected in reduced microvessel density in tumor xenografts.
|Cell lines||41 human NSCLC cell lines in vitro: A427, A549, Calu-1, Calu-3, Calu-6, H23, H226, H358, H460, H520, H522, H596, H810, H838, H1155, H1299, H1385, H1435, H1437, H1563, H1568, H1581, H1651, H1703, H1755, H1793, H1836, H1944, H1975, H2030, H2073, H2106, H2110, H2135, H2172, H2228, H2286, H2342, H2405, HCC827, and SHP77|
|Preparation method||Proliferation assays
Cells were seeded in duplicate at 5,000-10,000 cells per well. The day after plating (day 1), NVP-AUY922 was added at 1 µM and 2-fold dilutions over 12 concentrations. Data were compared to untreated controls. Cells were counted on the day drug was added and five days later and these two counts were compared. Cells were harvested by trypsinization and counted immediately using a Coulter Z2 particle counter (Beckman Coulter Inc, Fullerton, CA). Percent growth inhibition, defined as 100 × (1 - [generations in treated wells/generations in untreated controls]) was determined. Experiments were performed in duplicate. Error bars represent standard error for each experiment. Non-linear curve fitting was performed by fitting curves to data points using the Proc NLIN function in SAS for Windows version 9.2 (SAS Institute, Inc., Cary, NC) using a basic four-parameter sigmoid model. IC50 (concentration needed to prevent 50% of cell population doublings) and IC100 (complete inhibition of proliferation) were the summary outcome measures interpolated from the resulting curves.
|Incubation time||5 days|
|Animal models||BT-474 Breast cancer xenograft model Tumor Xenografts|
|Formulation||formulated in 60 mM lactic acid or 2.5% ethanol, 20% 50 mM tartaric acid, 77.5% (5% glucose in water [D5W] containing 1% Tween 80) vol/vol|
|Dosages||25 to 58 mg/kg once per week|
|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.
Novel HSP90 Inhibitor NVP-AUY922 enhances the anti-tumor effect of temsirolimus against oral squamous cell carcinoma.
Okui T et al. Curr Cancer Drug Targets. 2012 Sep 17. PMID: 23016912.
Targeting HSP90 by the novel inhibitor NVP-AUY922 reduces growth and angiogenesis of pancreatic cancer.
Moser C et al. Anticancer Res. 2012 Jul;32(7):2551-61. PMID: 22753713.
Heat shock protein-90 inhibitor, NVP-AUY922, is effective in combination with fludarabine against chronic lymphocytic leukemia cells cultured on CD40L-stromal layer and inhibits their activated/proliferative phenotype.
Best OG et al. Leuk Lymphoma. 2012 Nov;53(11):2314-20. PMID: 22646928.
The Hsp90 inhibitor NVP-AUY922-AG inhibits NF-κB signaling, overcomes microenvironmental cytoprotection and is highly synergistic with fludarabine in primary CLL cells.
Walsby E et al. Oncotarget. 2012 May;3(5):525-34. PMID: 22619113.
The HSP90 inhibitor NVP-AUY922 radiosensitizes by abrogation of homologous recombination resulting in mitotic entry with unresolved DNA damage.
Zaidi S et al. PLoS One. 2012;7(4):e35436. PMID: 22523597.
Strong anti-tumor effect of NVP-AUY922, a novel Hsp90 inhibitor, on non-small cell lung cancer.
Ueno T et al. Lung Cancer. 2012 Apr;76(1):26-31. PMID: 21996088.
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