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.

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.