NVP-AUY922: a small molecule HSP90 inhibitor with potent antitumor activity in preclinical breast cancer models

Jensen, Michael Rugaard; Schoepfer, Joseph; Radimerski, Thomas; Massey, Andrew; Guy, Chantale T.; Brueggen, Josef; Quadt, Cornelia; Buckler, Alan; Cozens, Robert; Drysdale, Martin J.; García‐Echeverría, Carlos; Chêne, Patrick

doi:10.1186/bcr1996

Cited by 209 publications

(169 citation statements)

References 31 publications

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“…VER-155008 binds in the ATPase site of Hsc70/Bag-1 and the adenosine portion of VER-155008 adopts corresponding protein interactions as the adenosine portion of ATP. The additional potency of VER-155008 is likely through the displacement of a water group and the We have previously shown that following Hsp90 inhibition with NVP-AUY922 or 17-AAG, deferential caspase dependent apoptotic responses are observed [26,27]. For example, the Her2 positive breast carcinoma BT474 undergoes massive caspase dependent apoptosis while the colon carcinoma cell line HCT116 does not.…”

Section: Ver-155008 Is a Potent Inhibitor Of The Hsp70 Family Of Chapmentioning

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

273

254

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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: Ver-155008 Is a Potent Inhibitor Of The Hsp70 Family Of Chapmentioning

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

273

254

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“…Significant antitumor activity was also observed when the compound was administered on a weekly i.v. schedule (Jensen et al, 2008). NVP-AUY922 has entered phase I clinical trials.…”

Section: Phospholipids-antagonists Of Ph Domainsmentioning

confidence: 99%

Drug discovery approaches targeting the PI3K/Akt pathway in cancer

2008

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“…Antitumor efficacy ranges from minimal effects to tumor growth stasis but rarely tumor regression (9,14,15,(18)(19)(20). The variance in response between xenograft models may be attributable to differences in client protein dependence on Hsp90, tumor dependence on the client protein, kinetics of client protein degradation, and resynthesis, as well as, drug pharmacokinetic and pharmacologic properties.…”

Section: Introductionmentioning

confidence: 99%

“…All other Hsp90 inhibitors are fully synthetic small molecules that fall into distinct structural classes including: (i) resorcinol-containing molecules (NVP-AUY922, KW-2478, STA-9090, and AT13387), (ii) purine scaffold (BIIB021, PU-H71, and MPC-3100), (iii) imidazopyridine (Debio 0932), (iv) 2-aminoterephthalamide (XL888), and (v) aminopyrimidine (NVP-HSP990). The chemical structures of BIIB028 and DS- 2248 have not yet been disclosed (5)(6)(7)(9)(10)(11)(12)(13)(14)(15)(16)(17).…”

Section: Introductionmentioning

confidence: 99%

“…Currently, 13 synthetic Hsp90 inhibitors are under assessment in oncology clinical trials. Six inhibitors (IPI-504, NVP-AUY922, KW-2478, STA-9090, AT13387, and BIIB-028) are administered intravenously, whereas 7 (BIIB-021, IPI-493, XL-888, MPC-3100, DS-2248, Debio 0932, and NVP-HSP990) are dosed orally (5)(6)(7)(9)(10)(11)(12)(13)(14)(15)(16)(17). These inhibitors address some key pharmaceutical limitations of 17-AAG (5-7).…”

Section: Introductionmentioning

confidence: 99%

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The Novel Oral Hsp90 Inhibitor NVP-HSP990 Exhibits Potent and Broad-spectrum Antitumor ActivitiesIn VitroandIn Vivo

Menezes

Taverna

Jensen

et al. 2012

Molecular Cancer Therapeutics

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A novel oral Hsp90 inhibitor, NVP-HSP990, has been developed and characterized in vitro and in vivo. In vitro, NVP-HSP990 exhibits single digit nanomolar IC 50 values on three of the Hsp90 isoforms (Hsp90a, Hsp90b, and GRP94) and 320 nanomolar IC 50 value on the fourth (TRAP-1), with selectivity against unrelated enzymes, receptors, and kinases. In c-Met amplified GTL-16 gastric tumor cells, NVP-HSP990 dissociated the Hsp90-p23 complex, depleted client protein c-Met, and induced Hsp70. NVP-HSP990 potently inhibited the growth of human cell lines and primary patient samples from a variety of tumor types. In vivo, NVP-HSP990 exhibits drug-like pharmaceutical and pharmacologic properties with high oral bioavailability. In the GTL-16 xenograft model, a single oral administration of 15 mg/kg of NVP-HSP990 induced sustained downregulation of c-Met and upregulation of Hsp70. In repeat dosing studies, NVP-HSP990 treatment resulted in tumor growth inhibition of GTL-16 and other human tumor xenograft models driven by well-defined oncogenic Hsp90 client proteins. On the basis of its pharmacologic profile and broad-spectrum antitumor activities, clinical trials have been initiated to evaluate NVP-HSP990 in advanced solid tumors.

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NVP-AUY922: a small molecule HSP90 inhibitor with potent antitumor activity in preclinical breast cancer models

Cited by 209 publications

References 31 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

Drug discovery approaches targeting the PI3K/Akt pathway in cancer

The Novel Oral Hsp90 Inhibitor NVP-HSP990 Exhibits Potent and Broad-spectrum Antitumor ActivitiesIn VitroandIn Vivo

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