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AUY922 (NVP-AUY922)

Potent Hsp90 inhibitor CAS# 747412-49-3

AUY922 (NVP-AUY922)

Catalog No. BCC2123----Order now to get a substantial discount!

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Chemical structure

AUY922 (NVP-AUY922)

3D structure

Chemical Properties of AUY922 (NVP-AUY922)

Cas No. 747412-49-3 SDF Download SDF
PubChem ID 10096043 Appearance Powder
Formula C26H31N3O5 M.Wt 465.5
Type of Compound N/A Storage Desiccate at -20°C
Synonyms Luminespib; AUY922; VER-52296
Solubility DMSO : ≥ 62 mg/mL (133.18 mM)
*"≥" means soluble, but saturation unknown.
Chemical Name (5Z)-N-ethyl-5-(4-hydroxy-6-oxo-3-propan-2-ylcyclohexa-2,4-dien-1-ylidene)-4-[4-(morpholin-4-ylmethyl)phenyl]-2H-1,2-oxazole-3-carboxamide
SMILES CCNC(=O)C1=C(C(=C2C=C(C(=CC2=O)O)C(C)C)ON1)C3=CC=C(C=C3)CN4CCOCC4
Standard InChIKey SWDZPNJZKUGIIH-QQTULTPQSA-N
Standard InChI InChI=1S/C26H31N3O5/c1-4-27-26(32)24-23(18-7-5-17(6-8-18)15-29-9-11-33-12-10-29)25(34-28-24)20-13-19(16(2)3)21(30)14-22(20)31/h5-8,13-14,16,28,30H,4,9-12,15H2,1-3H3,(H,27,32)/b25-20-
General tips For obtaining a higher solubility , please warm the tube at 37 ℃ and shake it in the ultrasonic bath for a while.Stock solution can be stored below -20℃ for several months.
We recommend that you prepare and use the solution on the same day. However, if the test schedule requires, the stock solutions can be prepared in advance, and the stock solution must be sealed and stored below -20℃. In general, the stock solution can be kept for several months.
Before use, we recommend that you leave the vial at room temperature for at least an hour before opening it.
About Packaging 1. The packaging of the product may be reversed during transportation, cause the high purity compounds to adhere to the neck or cap of the vial.Take the vail out of its packaging and shake gently until the compounds fall to the bottom of the vial.
2. For liquid products, please centrifuge at 500xg to gather the liquid to the bottom of the vial.
3. Try to avoid loss or contamination during the experiment.
Shipping Condition Packaging according to customer requirements(5mg, 10mg, 20mg and more). Ship via FedEx, DHL, UPS, EMS or other couriers with RT, or blue ice upon request.

Biological Activity of AUY922 (NVP-AUY922)

DescriptionAUY922 (NVP-AUY922) is a highly potent inhibitor of HSP90 for HSP90α/β with IC50 of 13 nM /21 nM.
TargetsHSP90αHSP90β    
IC5013 nM21 nM    

Protocol

Cell experiment: [1]

Cell lines

NCI-N87, SNU-216 and SNU-484 cells

Preparation method

The solubility of this compound in DMSO is >10 mM. General tips for obtaining a higher concentration: Please warm the tube at 37 °C for 10 minutes and/or shake it in the ultrasonic bath for a while.Stock solution can be stored below -20°C for several months.

Reacting condition

200 nM, 24 h

Applications

AUY922 reduced expression of client proteins. It decreased expression of receptor tyrosine kinases, such as VEGFR1, 2, 3 and PDGFR-α. It also decreased Akt and phospho-Akt in a dose-dependent manner. Besides that, AUY922 treatment resulted in decreased expression of HER-2 in NCI-N87 cells.

Animal experiment : [2]

Animal models

Athymic Nude-nu mice injected with BT-474 breast cancer xenograft

Dosage form

Intravenous acute administration, 30 mg/kg

Application

A significant effect of AUY922 on HSP90-p23 complex dissociation was observed at the 2- and 6-hour time points. From 16 and 24 hours after compound administration, HSP90-p23 complexes reassembled in the BT-474 xenografts. AUY922 also induced phospho-AKT level reduction.

Other notes

Please test the solubility of all compounds indoor, and the actual solubility may slightly differ with the theoretical value. This is caused by an experimental system error and it is normal.

References:

[1] Lee K H, Lee J H, Han S W, et al. Antitumor activity of NVP‐AUY922, a novel heat shock protein 90 inhibitor, in human gastric cancer cells is mediated through proteasomal degradation of client proteins. Cancer science, 2011, 102(7): 1388-1395.

[2] Jensen M R, Schoepfer J, Radimerski T, et al. NVP-AUY922: a small molecule HSP90 inhibitor with potent antitumor activity in preclinical breast cancer models. Breast Cancer Res, 2008, 10(2): R33.

AUY922 (NVP-AUY922) Dilution Calculator

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Preparing Stock Solutions of AUY922 (NVP-AUY922)

1 mg 5 mg 10 mg 20 mg 25 mg
1 mM 2.1482 mL 10.7411 mL 21.4823 mL 42.9646 mL 53.7057 mL
5 mM 0.4296 mL 2.1482 mL 4.2965 mL 8.5929 mL 10.7411 mL
10 mM 0.2148 mL 1.0741 mL 2.1482 mL 4.2965 mL 5.3706 mL
50 mM 0.043 mL 0.2148 mL 0.4296 mL 0.8593 mL 1.0741 mL
100 mM 0.0215 mL 0.1074 mL 0.2148 mL 0.4296 mL 0.5371 mL
* Note: If you are in the process of experiment, it's necessary to make the dilution ratios of the samples. The dilution data above is only for reference. Normally, it's can get a better solubility within lower of Concentrations.

Research Update of AUY922 (NVP-AUY922)

1. Inhibition of HSP90 with AUY922 induces synergy in HER2-amplified trastuzumab-resistant breast and gastric cancer. Mol Cancer Ther. 2013 Apr;12(4):509-19. doi: 10.1158/1535-7163.MCT-12-0507. Epub 2013 Feb 8.
Abstract
The mono-therapy of AUY922 in the low nanomolar range potently inhibited proliferation of human gastric and breast cancer cells exhibiting a greater sensitivity to HER2-amplified cells than HER2-negative cells; while the combination of AUY922 and trastuzumab showed synergistic anticancer effect in conditioned trastuzumab-resistant models.
2. Novel Hsp90 inhibitor NVP-AUY922 radiosensitizes prostate cancer cells. Cancer Biol Ther. 2013 Apr;14(4):347-56. doi: 10.4161/cbt.23626. Epub 2013 Jan 28.
Abstract
AUY922 greatly increased the sensitivity of prostate cancer cells, Myc-CaP and PC3, to radiation and worked synergistically with radiation to increase apoptotic cell death, induce G2-M arrest, affect client protein expression and delay tumor growth.
3. The HSP90 inhibitor NVP-AUY922 potently inhibits non-small cell lung cancer growth. Mol Cancer Ther. 2013 Jun;12(6):890-900. doi: 10.1158/1535-7163.MCT-12-0998. Epub 2013 Mar 14.
Abstract
AUY922 ont only exhibited potent anticancer activity against NSCLC cells with IC50 and IC100 of 100 and 40 nmol/L respectively but also affected expression of genes involved in various cellular functions including decreased dihydrofolate reductase, where exposure to AUY922 stably slowed growth of A549 xenografts and decreased the expression of EGFR protein in H1975 xenografts.
4. The HSP90 inhibitor NVP-AUY922-AG inhibits the PI3K and IKK signalling pathways and synergizes with cytarabine in acute myeloid leukaemia cells. Br J Haematol. 2013 Apr;161(1):57-67. doi: 10.1111/bjh.12215. Epub 2013 Jan 29.
Abstract
NVP-AUY922-AG alone or synergistically with Ara-C exhibited anti-cancer activity against myeloid cell lines and primary AML blasts with significantly less toxicity to normal bone marrow, in which it induced increases in HSP70 expression and depletion of total AKT, IKKα and IKKβ.
5. Antiproliferative effect of the HSP90 inhibitor NVP-AUY922 is determined by the expression of PTEN in esophageal cancer. Oncol Rep. 2013 Jan;29(1):45-50. doi: 10.3892/or.2012.2074. Epub 2012 Oct 9.
Abstract
NVP-AUY922 significantly suppressed the activity of AKT and ERK and potently induced antiproliferation in ESCC cells, which are negatively associated with PETN expression.

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Background on AUY922 (NVP-AUY922)

AUY922 (NVP-AUY922) is a potent, novel synthetic resorcinylic isoxazole amide inhibitor of heat shock protein 90 (HSP90).[1] It is a small molecular with the formula of C26H31N3O5 and molecular weight of 465.5. It has a much higher affinity for Hsp90 and can be ound to the ATP binding site of Hsp90 at the N-terminal domain.[2] Heat shock protein 90 (HSP90) is a molecular chaperone essential for the stability of key regulators of cell growth and survival. NVP-AUY922 potently inhibits the proliferation of gastric cancer cell lines with with GI50 values of approximately 2 to 40 nmol/L and significantly induces the degradation of growth factor receptors and other client proteins.[3]

References:

[1] Suzanne A. E, Andy M, Florence I. R, et al. NVP-AUY922: A Novel Heat Shock Protein 90 Inhibitor Active against Xenograft Tumor Growth, Angiogenesis, and Metastasis. Cancer Res. 2008, 68. 2850-2860.

[2] Tsuyoshi U, Kazunori T, Shinichi T, Midori A, Munenori T, et al. Strong anti-tumor effect of NVP-AUY922, a novel Hsp90 inhibitor, on non-small cell lung cancer. Lung Cancer. 2012, 76. 26-31.

[3] Kyung-Hun L, Ju-Hee L, Sae-Won H, Seock-Ah I, et al. Antitumor activity of NVP-AUY922, a novel heat shock protein 90 inhibitor, in human gastric cancer cells is mediated through proteasomal degradation of client proteins. Cancer Sci. 2011, 102. 1388–1395.

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References on AUY922 (NVP-AUY922)

Dual PI3K- and mTOR-inhibitor PI-103 can either enhance or reduce the radiosensitizing effect of the Hsp90 inhibitor NVP-AUY922 in tumor cells: The role of drug-irradiation schedule.[Pubmed:27224913]

Oncotarget. 2016 Jun 21;7(25):38191-38209.

Inhibition of Hsp90 can increase the radiosensitivity of tumor cells. However, inhibition of Hsp90 alone induces the anti-apoptotic Hsp70 and thereby decreases radiosensitivity. Therefore, preventing Hsp70 induction can be a promising strategy for radiosensitization. PI-103, an inhibitor of PI3K and mTOR, has previously been shown to suppress the up-regulation of Hsp70. Here, we explore the impact of combining PI-103 with the Hsp90 inhibitor NVP-AUY922 in irradiated glioblastoma and colon carcinoma cells. We analyzed the cellular response to drug-irradiation treatments by colony-forming assay, expression of several marker proteins, cell cycle progression and induction/repair of DNA damage. Although PI-103, given 24 h prior to irradiation, slightly suppressed the NVP-AUY922-mediated up-regulation of Hsp70, it did not cause radiosensitization and even diminished the radiosensitizing effect of NVP-AUY922. This result can be explained by the activation of PI3K and ERK pathways along with G1-arrest at the time of irradiation. In sharp contrast, PI-103 not only exerted a radiosensitizing effect but also strongly enhanced the radiosensitization by NVP-AUY922 when both inhibitors were added 3 h before irradiation and kept in culture for 24 h. Possible reasons for the observed radiosensitization under this drug-irradiation schedule may be a down-regulation of PI3K and ERK pathways during or directly after irradiation, increased residual DNA damage and strong G2/M arrest 24 h thereafter. We conclude that duration of drug treatment before irradiation plays a key role in the concomitant targeting of PI3K/mTOR and Hsp90 in tumor cells.

2-phenylethynesulphonamide (PFT-mu) enhances the anticancer effect of the novel hsp90 inhibitor NVP-AUY922 in melanoma, by reducing GSH levels.[Pubmed:26988132]

Pigment Cell Melanoma Res. 2016 May;29(3):352-71.

Heat shock proteins (HSPs), are molecular chaperones that assist the proper folding of nascent proteins. This study aims to evaluate the antitumour effects of the hsp90 inhibitor NVP-AUY922 in melanoma, both in vitro and in vivo. Our results show that NVP-AUY922 inhibits melanoma cell growth in vitro, with down regulation of multiple signalling pathways involved in melanoma progression such as NF-kB and MAPK/ERK. However, NVP-AUY922 was unable to limit tumour growth in vivo. Cotreatment of A375M xenografts with NVP-AUY922 and PFT-mu, a dual inhibitor of both hsp70 and autophagy, induced a synergistic increase of cell death in vitro, and delayed tumour formation in A375M xenografts. PFT-mu depleted cells from the reduced form of glutathione (GSH) and increased oxidative stress. The oxidative stress induced by PFT-mu further enhanced NVP-AUY922-induced cytotoxic effects. These data suggest a potential therapeutic role for NVP-AUY922 used in combination with PFT-mu, in melanoma.

The HSP90 inhibitor, NVP-AUY922, sensitizes KRAS-mutant non-small cell lung cancer with intrinsic resistance to MEK inhibitor, trametinib.[Pubmed:26723875]

Cancer Lett. 2016 Mar 1;372(1):75-81.

RAS-driven tumors are often difficult to treat with conventional therapies and therefore, novel treatment strategies are necessary. The present study describes a promising targeted therapeutic strategy against non-small cell lung cancer (NSCLC) harboring KRAS mutations, which has intrinsic resistance to MEK inhibition. Results showed that intrinsic resistance to MEK inhibition occurred via high AKT expression by PI3K activation as a bypass pathway. The HSP90 inhibitor AUY922 suppressed PI3K-AKT-mTOR and RAF-MEK-ERK, and rendered cells sensitive to trametinib (GSK1120212). Synergy from the combination of the two drugs was observed in only sub-therapeutic concentrations of either drug. Dual inhibition of the HSP90 and MEK signaling pathways with sub-therapeutic doses may represent a potent therapeutic strategy to treat KRAS-mutant NSCLC with intrinsic resistance to MEK inhibition and to resolve the toxicity observed upon dual inhibition of AKT and MEK at therapeutic doses in clinical trials.

The novel HSP90 inhibitor NVP-AUY922 shows synergistic anti-leukemic activity with cytarabine in vivo.[Pubmed:26748184]

Exp Cell Res. 2016 Jan 15;340(2):220-6.

HSP90 is a molecular chaperone essential for stability, activity and intracellular sorting of many proteins, including oncoproteins, such as tyrosine kinases, transcription factors and cell cycle regulatory proteins. Therefore, inhibitors of HSP90 are being investigated for their potential as anti-cancer drugs. Here we show that the HSP90 inhibitor NVP-AUY922 induced degradation of the fusion oncoprotein FOP2-FGFR1 in a human acute myeloid leukemia (AML) cell line, KG-1a. Concordantly, downstream signaling cascades, such as STAT1, STAT3 and PLCgamma were abrogated. At concentrations that caused FOP2-FGFR1 degradation and signaling abrogation, NVP-AUY922 treatment caused significant cell death and inhibition of proliferation of KG-1a cells in vitro. In an animal model for AML, NVP-AUY922 administrated alone showed no anti-leukemic activity. However, when NVP-AUY922 was administered in combination with cytarabine, the two compounds showed significant synergistic anti-leukemic activity in vivo. Thus NVP-AUY922 and cytarabine combination therapy might be a prospective strategy for AML treatment.

Description

Luminespib (NVP-AUY922) is a potent HSP90 inhibitor with IC50s of 7.8 and 21 nM for HSP90α and HSP90β, respectively.

Keywords:

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