NVP-AUY922: A Novel Heat Shock Protein 90 Inhibitor Active against Xenograft Tumor Growth, Angiogenesis, and Metastasis

Eccles, Suzanne A.; Massey, Andy; Raynaud, Florence I.; Sharp, Swee Y.; Box, Gary; Valenti, Melanie; Patterson, Lisa; Brandon, Alexis de Haven; Gowan, Sharon; Boxall, Frances; Aherne, Wynne; Rowlands, Martin; Hayes, Angela; Martins, Vanessa; Urban, Frederique; Boxall, Kathy; Prodromou, Chrisostomos; Pearl, Laurence H.; James, Karen; Matthews, Thomas P.; Cheung, Kwai-Ming J.; Kalusa, Andrew; Jones, Keith; McDonald, Edward; Barril, Xavier; Brough, Paul A.; Cansfield, Julie E.; Dymock, Brian; Drysdale, Martin J.; Finch, Harry; Howes, Rob; Hubbard, Roderick E.; Surgenor, Alan; Webb, Paul; Wood, Mike; Wright, Lisa; Workman, Paul

doi:10.1158/0008-5472.can-07-5256

Cited by 434 publications

(447 citation statements)

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“…Client protein degradation was determined by western blotting as previously described [26]. Her2 (ab8054, Abcam), Raf-1 (sc-133, Santa Cruz Biotechnology), and Hsp70 (SPA-810, StressGen) relative levels were determined using ECL (GE Bioscience).…”

Section: Client Protein Degradation Analysismentioning

confidence: 99%

A novel, small molecule inhibitor of Hsc70/Hsp70 potentiates Hsp90 inhibitor induced apoptosis in HCT116 colon carcinoma cells

Massey¹,

Williamson²,

Browne³

et al. 2009

Cancer Chemother Pharmacol

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Purpose The anti-apoptotic function of the 70 kDa family of heat shock proteins and their role in cancer is well documented. Dual targeting of Hsc70 and Hsp70 with siRNA induces proteasome-dependent degradation of Hsp90 client proteins and extensive tumor specific apoptosis as well as the potentiation of tumor cell apoptosis following pharmacological Hsp90 inhibition. Methods We have previously described the discovery and synthesis of novel adenosine-derived inhibitors of the 70 kDa family of heat shock proteins; the first inhibitors described to target the ATPase binding domain. The in vitro activity of VER-155008 was evaluated in HCT116, HT29, BT474 and MDA-MB-468 carcinoma cell lines. Cell proliferation, cell apoptosis and caspase 3/7 activity was determined for VER-155008 in the absence or presence of small molecule Hsp90 inhibitors. Results VER-155008 inhibited the proliferation of human breast and colon cancer cell lines with GI 50 s in the range 5.3-14.4 lM, and induced Hsp90 client protein degradation in both HCT116 and BT474 cells. As a single agent, VER-155008 induced caspase-3/7 dependent apoptosis in BT474 cells and non-caspase dependent cell death in HCT116 cells. VER-155008 potentiated the apoptotic potential of a small molecule Hsp90 inhibitor in HCT116 but not HT29 or MDA-MB-468 cells. In vivo, VER-155008 demonstrated rapid metabolism and clearance, along with tumor levels below the predicted pharmacologically active level. Conclusion These data suggest that small molecule inhibitors of Hsc70/Hsp70 phenotypically mimic the cellular mode of action of a small molecule Hsp90 inhibitor and can potentiate the apoptotic potential of a small molecule Hsp90 inhibitor in certain cell lines. The factors determining whether or not cells apoptose in response to Hsp90 inhibition or the combination of Hsp90 plus Hsc70/ Hsp70 inhibition remain to be determined.

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Section: Client Protein Degradation Analysismentioning

confidence: 99%

A novel, small molecule inhibitor of Hsc70/Hsp70 potentiates Hsp90 inhibitor induced apoptosis in HCT116 colon carcinoma cells

Massey¹,

Williamson²,

Browne³

et al. 2009

Cancer Chemother Pharmacol

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266

254

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“…AUY922 has excellent cellular potency against a panel of tumor cell lines (Brough et al, 2008;Eccles et al, 2008;Stuhmer et al, 2008). In addition, optimization of pharmacokinetic properties led to robust therapeutic responses in a wide variety of human tumor xenografts tightly linked to high intratumor concentrations of compound and phamacodynamic response (Eccles et al, 2008). The promising preclinical data obtained with AUY922 supported the initiation of clinical phase I trials in patients with solid tumors.…”

Section: Discussionmentioning

confidence: 95%

“…AUY922 is a most potent resorcinylic isoxazole amide HSP90 inhibitor, which binds to the adenosine triphosphate-binding pocket of HSP90 (Brough et al, 2008). AUY922 has excellent cellular potency against a panel of tumor cell lines (Brough et al, 2008;Eccles et al, 2008;Stuhmer et al, 2008). In addition, optimization of pharmacokinetic properties led to robust therapeutic responses in a wide variety of human tumor xenografts tightly linked to high intratumor concentrations of compound and phamacodynamic response (Eccles et al, 2008).…”

Section: Discussionmentioning

confidence: 99%

“…NVP-AUY922 is a novel 4,5-diaryloxazole adenosine triphosphate-binding site heat shock protein 90 (HSP90) inhibitor, which has been shown to inhibit the chaperone function of HSP90 and deplete the levels of HSP90 client protein (for example, ErbB2, Akt, Raf and BcrAbl) (Brough et al, 2008;Eccles et al, 2008;Stuhmer et al, 2008). Combining AUY922 with ABL kinase inhibitors may provide several advantages, such as enhanced efficacy and reducing the potential emergence of new resistant mutations.…”

Section: Introductionmentioning

confidence: 99%

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Combined effects of novel heat shock protein 90 inhibitor NVP-AUY922 and nilotinib in a random mutagenesis screen

et al. 2011

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To overcome imatinib resistance, more potent ABL tyrosine kinase inhibitors (TKIs), such as nilotinib and dasatinib have been developed, with demonstrable preclinical activity against most imatinib-resistant BCR-ABL kinase domain mutations, with the exception of T315I. However, imatinib-resistant patients already harboring mutations have a higher likelihood of developing further mutations under the selective pressure of potent ABL TKIs. NVP-AUY922 (Novartis) is a novel 4,5-diaryloxazole adenosine triphosphate-binding site heat shock protein 90 (HSP90) inhibitor, which has been shown to inhibit the chaperone function of HSP90 and deplete the levels of HSP90 client protein including BCR-ABL. In this study, we investigated the combined effects of AUY922 and nilotinib on random mutagenesis for BCR-ABL mutation (Blood, 109; 5011, 2007). Compared with single agents, combination with AUY922 and nilotinib was more effective at reducing the outgrowth of resistant cell clones. No outgrowth was observed in the presence of 2 lM of nilotinib and 20 nM of AUY922. The observed data from the isobologram indicated the synergistic effect of simultaneous exposure to AUY922 and nilotinib even in BaF3 cells expressing BCR-ABL mutants including T315I. In vivo studies also demonstrated that the combination of AUY922 and nilotinib prolonged the survival of mice transplanted with mixture of BaF3 cells expressing wild-type BCR-ABL and mutant forms. Taken together, this study shows that the combination of AUY922 and nilotinib exhibits a desirable therapeutic index that can reduce the in vivo growth of mutant forms of BCR-ABL-expressing cells.

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“…The isoxazole derivatives NVP-AUY922, 59 PU-H71, 60 CUDC-305 61 and BIIB021 (CNF2024) 62 are Hsp90 inhibitors that have been tested clinically. 17-AAG and other benzoquinone ansamycins are inactive in P-glycoprotein/MRP-1-expressing tumors, but BIIB021 is active independently of NQO1/DT-diaphorase and P-glycoprotein expression.…”

Section: Actions Ofmentioning

confidence: 99%

Molecular basis for the actions of Hsp90 inhibitors and cancer therapy

et al. 2011

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Heat-shock protein 90 (Hsp90) inhibitor downregulates c-Myc expression and upregulates the expression of tumor repressor proteins such as p53 and pRB, inhibiting the G1/S transition and causing G2/M arrest during cell cycle progression. The cycle progression is extensively controlled by the pRB/E2F signaling pathway. E2F is released from the pRB/E2F complex with the phosphorylation of pRB by cyclin-cyclin-dependent kinase (CDK) complexes. The released E2F promotes the transcription of target genes involved in cell cycle progression. The pRB/E2F signaling pathway is controlled by DNA methyltransferase-1 (Dnmt-1). The elevated expression of Dnmt-1 has been reported in carcinomas of the colon, lung and prostate. A defect of pRB expression in RbÀ/À cancer cells is caused by the aberrant methylation of CpG in the Rb promoter. The Hsp90 inhibitor disrupts the Dnmt-1/Hsp90 association and upregulates pRB expression. In this review, the Hsp90 inhibitors that show promise for cancer therapy are summarized.

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NVP-AUY922: A Novel Heat Shock Protein 90 Inhibitor Active against Xenograft Tumor Growth, Angiogenesis, and Metastasis

Cited by 434 publications

References 46 publications

A novel, small molecule inhibitor of Hsc70/Hsp70 potentiates Hsp90 inhibitor induced apoptosis in HCT116 colon carcinoma cells

A novel, small molecule inhibitor of Hsc70/Hsp70 potentiates Hsp90 inhibitor induced apoptosis in HCT116 colon carcinoma cells

Combined effects of novel heat shock protein 90 inhibitor NVP-AUY922 and nilotinib in a random mutagenesis screen

Molecular basis for the actions of Hsp90 inhibitors and cancer therapy

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