HSP90α (IC50 = 7.8 nM); HSP90β (IC50 = 21 nM); GRP94 (IC50 = 535 nM); TRAP-1 (IC50 = 85 nM)

Luminespib inhibits HSP90 effectively and selectively, with IC50s and Kis of 21 ± 16, 8.2 ± 0.7 nM for HSP90β and 7.8 ± 1.8, 9.0 ± 5.0 nM for HSP90α. Luminespib has weak activity against GRP94 and TRAP-1, with IC50 values of 535 ± 51 nM (Ki, 108 nM) and 85 ± 8 nM (Ki, 53 nM), respectively. Luminespib inhibits the proliferation of various human tumor cell lines (2.3–49.6 nM), induces cell cycle arrest and apoptosis, and depletes client proteins in human cancer cells (80 nM)[1]. Luminespib (100 nM) significantly reduces CD40L fibroblast-induced changes in immunophenotype and STAT3 signaling while having no effect on the viability of CLL cells. Luminespib (500 nM) in combination with NSC 118218 induces apoptosis in co-culture cells more effectively than either drug alone, and it overcomes fibroblast resistance to Hsp90 inhibitors[2]. Luminespib shows great inhibition of pancreatic cancer cells with an IC50 of 10 nM. Luminespib (10 nM) significantly inhibits pancreatic cancer cell migration and invasion in both the absence and presence of EGF [3].

In human tumor xenografts, luminipespib (50, 75 mg/kg, ip) effectively suppresses the rate of tumor growth, lowering the mean weights of tumors on day 11[2]. In the L3.6pl pancreatic cancer cell-bearing mice model, luminescein (50 mg/kg/week, 3×25 mg/kg/week) dramatically lowers tumor weights and tumor growth rates[3].

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Effects of Luminespib/NVP-AUY922 on growth and vascularization of pancreatic cancer cells in vivo. To estimate growth-inhibitory and antiangiogenic effects of NVP-AUY922 in vivo, we first used a subcutaneous tumor model (L3.6pl cells). Treatment with NVP-AUY922 (50 mg/kg/week or 3×25 mg/kg/week) significantly reduced the growth of pancreatic tumors, compared to that in controls (Figure 6A). This reduction in tumor growth was also reflected in the final weights of excised tumors on day 17, which were significantly lower in the NVP-AUY922-treated groups (Figure 6B).
To test whether HSP90 inhibition with Luminespib/NVP-AUY922 indeed reduces pancreatic cancer growth in the appropriate tumor microenvironment in vivo, we subsequently used an orthotopic model of pancreatic cancer (L3.6pl cells). Mice received either NVP-AUY922 (50 mg/kg) or vehicle, starting on day 7 post tumor cell implantation. On day 26, the experiment was terminated as mice in the control group became moribund because of tumor burden. Analysis of pancreatic tumor burden (tumor volume and tumor weight) shows that mice in the NVP-AUY922 therapy arm had developed significantly smaller tumors as compared to mice in the control group (Figure 6C and D). Importantly, mouse body weights did not statistically differ between these two groups. In addition, vascularization of L3.6pl tumors in terms of CD31-positive vessel area was significantly reduced in tumor sections of the NVP-AUY922-treated group. In conclusion, these results show that NVP-AUY922 substantially inhibits in vivo growth of pancreatic cancer through direct effects on tumor cells, and also through inhibition of angiogenesis.[3]

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Daily dosing of Luminespib/NVP-AUY922 (50 mg/kg i.p. or i.v.) to athymic mice generated peak tumor levels at least 100-fold above cellular GI(50). This produced statistically significant growth inhibition and/or regressions in human tumor xenografts with diverse oncogenic profiles: BT474 breast tumor treated/control, 21%; A2780 ovarian, 11%; U87MG glioblastoma, 7%; PC3 prostate, 37%; and WM266.4 melanoma, 31%. [1]
NVP-AUY922 inhibits HSP90 and exhibits potent antitumor efficacy in human tumor xenografts. Following five daily i.p. doses of 50 mg/kg NVP-AUY922 to athymic mice bearing BRAF mutant WM266.4 melanoma xenografts, liquid chromatography-tandem mass spectrometry analysis indicated NVP-AUY922 concentrations of 6.8 to 7.7 μmol/L in tumors over 24 h (Supplementary Table S3). As quantified by electrochemiluminescent immunoassay, ERBB2 levels were reduced to a nadir of 7.3% of controls at 6 h, remaining below 35% over 24 h. Phospho-ERK1/2 levels were 65% to 83%, phospho-AKT levels were 13% to 51%, AKT levels were 57% to 65%, and HIF-1α levels were 60% to 85%. HSP72 expression was increased to 247% to 281% of controls over the 24-h period. [1]
The therapeutic effect of Luminespib/NVP-AUY922 was determined against established WM266.4 melanoma xenografts. Daily doses of 75 mg/kg caused ∼10% body weight loss; thus, doses were reduced to 50 mg/kg/d after eight doses and body weights rapidly recovered. NVP-AUY922 significantly inhibited tumor growth rate, reducing the mean weights of tumors on day 11 from 252 ± 19 mg in controls to 78 ± 6 mg (Fig. 5A). Tumor samples on day 11 (24 h after the final dose) showed the HSP90 inhibition signature of depleted ERBB2 and CDK4, with induced HSP72 (Fig. 5B).[1]
Researchers next tested 50 mg/kg Luminespib/NVP-AUY922 given i.p. or i.v. daily against established WM266.4 melanoma xenografts. The treatment regimens were well tolerated with either no (i.p.) or <5% (i.v.) differences in mean body weights compared with controls. Tumor weights after 9 days of treatment were reduced by 55% in the i.v. group (P = 0.000085) and by 46% in the i.p. group (P = 0.00067) compared with controls. Biomarker changes confirmed HSP90 inhibition in tumor as in the previous study. Both routes of administration gave comparable levels of NVP-AUY922 in the tumors (similar to those reported above in the single dose studies), consistent with the comparable efficacy and pharmacodynamic changes observed. In three additional studies, mice with established WM266.4 tumors were treated with different schedules of NVP-AUY922, and in all cases, significant growth delays were observed, with some recovery of growth rate toward the end of dosing (Supplementary Table S5). [1]
Researchers also tested the ability of Luminespib/NVP-AUY922 to inhibit established disseminated melanoma. Therapy commenced 7 days after i.v. injection of WM266.4 melanoma cells and continued for 32 days (50 mg/kg five times weekly for 18 days, three times weekly for a further 14 days). Histologic examination of lungs indicated that both the number and size of lung metastases were decreased by NVP-AUY922 treatment (Fig. 5C). The mean number of metastases was reduced from 61 ± 13 to 17 ± 3 (72% inhibition; P = 0.0037) and the total area occupied by the metastases decreased from 2.38 ± 0.43 mm2 to 0.15 ± 0.04 mm2 (93.7% inhibition; P = 0.0003) as shown in Fig. 5D. [1]
Researchers then determined the efficacy of Luminespib/NVP-AUY922 in established PTEN-null U87MG human glioblastoma xenografts. Again, highly significant growth inhibition was obtained; indeed, regressions were observed because mean tumor volumes on day 18 were decreased to 58% of day 0 values (Fig. 6A). HSP90 inhibition was confirmed by Western blot with significant depletion of ERBB2, AKT, phospho-ERK1/2, HIF-1α, and survivin together with increased HSP72 (data not shown). We also showed clear depletion of phospho-AKT (Ser473) and phospho-S6 (Ser240/244) in histologic sections, consistent with inhibition of the phosphatidylinositol 3-kinase (PI3K) pathway (Fig. 6B). Figure 6C shows that levels of HIF-1α and AKT were decreased to 39% and 27% of controls, respectively, and HSP72 levels increased by ∼800% as measured by electrochemiluminescent immunoassay. Finally, microvessel density was significantly reduced in NVP-AUY922–treated tumors, suggesting an antiangiogenic effect (Fig. 6D). [1]
A parallel pharmacokinetic/pharmacodynamic study of five daily doses (50 mg/kg i.p., comparable with that described above for WM266.4) was performed in U87MG xenografts. Mean tumor NVP-AUY922 concentrations were 3.8 to 6.7 μmol/L from 6 to 24 h following the last dose (Supplementary Table S4). Phospho-AKT expression was reduced to 19% to 56%, AKT to 74% to 80%, and HIF-1α to 32% to 48% of controls over 6 to 24 h. Phospho-ERK1/2 levels were apparently not decreased in this tumor but HSP72 expression was increased to 228% to 530% of controls (data not shown). [1]
The therapeutic efficacy of Luminespib/NVP-AUY922 was explored in further human tumor xenografts of varying histogenic origins and with differing molecular abnormalities. Strong inhibitory effects were obtained in the PTEN and PIK3CA mutant A2780 ovarian carcinoma [treated/control (T/C) of 10.5% after 8 daily treatments with 50 mg/kg i.p.; Supplementary Fig. S5A] and the ERBB2+ ERα+ BT474 breast carcinoma (T/C of 21% after 24 daily treatments; Supplementary Fig. S5B). In the latter case, regressions were observed in 5 of 12 tumors. Body weight loss was <5% and clear biomarker changes consistent with HSP90 inhibition were obtained in both studies (Supplementary Fig. S5C and D). In BT474, complete loss of ERBB2 and substantial depletion of ERα were shown, in addition to reductions in CDK4 and phospho-ERK1/2. Finally, Researchers explored the ability of Luminespib/NVP-AUY922 (50 mg/kg daily i.p.) to inhibit growth and spontaneous metastasis in an established orthotopic and metastatic PTEN-null human prostate carcinoma xenograft model (PC3LN3). Primary tumor growth was reduced (Supplementary Fig. S6A), as was the incidence and mass of local lymph node metastases (Supplementary Fig. S6B). Fifty-three percent of control animals developed distant lymph node metastases, but none was detected in the NVP-AUY922–treated animals. Western blots showed induction of HSP72, strong depletion of ERBB2, and weak but detectable depletion of CDK4 (Supplementary Fig. S6C). The antitumor activity of NVP-AUY922 in all human tumor xenograft models tested is summarized in Supplementary Table S5.

Profiling against a panel of kinases was carried out and screening against a panel of additional enzymes and receptors was performed at Cerep. X-ray crystallography, fluorescence polarization, and isothermal calorimetry were as described [1].

Molecular biomarkers and tumor cell and endothelial cell activities. [1]
Effects of Luminespib/NVP-AUY922 on the expression of client proteins [e.g., CRAF, BRAF, cyclin-dependent kinase 4 (CDK4), ERBB2, AKT, and vascular endothelial growth factor receptor 2 (VEGFR2)] and on induction of HSP72 were determined in human tumor and endothelial cells. Tumor cell chemotaxis, haptotaxis, invasion, and endothelial cell functions related to angiogenesis were also determined as described with minor variations (see figure legends).

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Measurement of Luminespib/NVP-AUY922 in biological samples. [1]
Microsomal incubations were performed with mouse and human liver preparations and human carcinoma cell uptake studies were as described. Given the relatively low GI50 for NVP-AUY922 in HCT116 colon carcinoma cells, we used 5 × GI50 for cell uptake studies and equimolar concentrations in HT29 cells.[1]

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3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide analyses. [3]
To evaluate the cytotoxic potential of Luminespib/NVP-AUY922, pancreatic cancer cells, as well as HUVECs and VSMCs, were seeded into 96-well plates (1×103 cells per well) and exposed to different concentrations of NVP-AUY922 for the indicated times at 37°C. Respective concentrations of DMSO were added to controls accordingly. The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay was used to assess cell viability, as previously described.

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Immunoblot analysis of signaling intermediates. [3]
To determine the effects of Luminespib/NVP-AUY922 on signaling intermediates, western blot analysis was performed. Experiments were carried out in triplicates. Unless otherwise indicated, cells were incubated with NVP-AUY922 (10 nmol/l) for 20 h before stimulation with EGF (40 ng/ml), VEGF-A (50 ng/ml), or PDGF-B (10 ng/ml). Whole cell lysates and nuclear extracts were prepared as described elsewhere. Protein samples (75 μg) were subjected to western blotting using a denaturing 10% sodium dodecyl sulfate polyacrylamide gel. Membranes were sequentially probed with antibodies specific for phospho-MEK, MEK, phospho-AKTSer473, AKT, phospho-ERKThr202/Tyr204, ERK, phospho-signal transducer and activator of transcription (STAT)3Tyr705, STAT3, HSP70, HER-2, cMET, focal adhesion kinase (FAK); phospho-VEGF-R2, VEGF-R2, phospho-PDGF-Rβ, PDGF-Rβ, β-Actin; and HIF-1α). Antibodies were detected by enhanced chemiluminescence. Western blot analyses of tumor tissue samples were carried out likewise after tissue lysis using an extraction buffer, as described elsewher.

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Motility assays. [3]
To determine the effects of Luminespib/NVP-AUY922 (10 nmol/l) on cell motility in vitro, migration and invasion assays were performed using modified Boyden chambers, as described elsewhere. Briefly, 1×105 cells were resuspended in 1% FCS-DMEM and seeded into uncoated (migration) or coated (invasion) inserts with 8-mm filter pores, and 10% FCS-DMEM, with or without EGF (40 ng/ml), VEGF-A (50 ng/ml) or PDGF-B (10 ng/ml), serving as chemoattractants. After 24 h and 48 h, cells were fixed and migrated cells were stained. Cells were counted in four random fields, and average numbers were calculated.

Xenograft pharmacokinetic and efficacy studies. [1]
In vivo pharmacokinetic studies in female NCr athymic mice bearing WM266.4 human melanoma xenografts were essentially as described. Luminespib/NVP-AUY922 was dissolved in DMSO and diluted in sterile saline/Tween 20. A single dose of 50 mg/kg Luminespib/NVP-AUY922 was given i.v. or i.p. and groups of three animals were taken at intervals for pharmacokinetic analyses. Further details are in Supplementary information.
For efficacy studies, human tumor xenografts were established s.c. in athymic mice. WM266.4 cells were also injected i.v. to generate experimental lung metastases and PC3LN3 prostate carcinoma cells were implanted into the prostates of male mice. Dosing with Luminespib/NVP-AUY922 commenced when tumors were well established using schedules described. Tumor growth was monitored and at study end samples were harvested for analysis. Further details are provided in Supplementary information.

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Animal models. [1]
Eight-week-old male athymic nude mice (BALB/cnu/nu) were used for experiments. The effects of HSP90 inhibition on the growth of human pancreatic cancer cells (L3.6pl) were first investigated in a subcutaneous tumor model. Cancer cells (1×106) were injected into the subcutis of the right flank of nude mice. Mice were randomized (n=10 per group) and assigned to treatment groups. Intraperitoneal injections of Luminespib/NVP-AUY922 (50 mg/kg/week or 3×25 mg/kg/week) were started on day 7 after tumor cell implantation, when tumors became palpable. Tumor diameters were measured every other day and tumor volumes were calculated (width2×length× 0.5). On day 17 after tumor cell inoculation, mice were sacrificed and excised tumors were measured and weighed.
The effects of HSP90 inhibition by Luminespib/NVP-AUY922 were additionally evaluated in an orthotopic pancreatic cancer model. In brief, 5×105 human pancreatic cancer cells (L3.6pl) were injected into the pancreas of mice. Tumors were allowed to grow for seven days after implantation before treatment was initiated. Mice were randomized into groups (n=10 per group), receiving either vehicle (saline) or Luminespib/NVP-AUY922 (50 mg/kg/week) by i.p. injections. On day 26 after tumor cell inoculation, the experiment was terminated and excised tumors were measured and weighed. For immunohistochemical analyses, tumors were either paraffin embedded or placed in optimum cutting temperature (OCT) solution.

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Dissolved in DMSO and diluted in sterile saline/Tween 20; 50 mg/kg; i.p. and i.v. injection

Female NCr athymic mice bearing WM266.4 human melanoma xenografts

NVP-AUY922 shows limited metabolism and favorable pharmacokinetics. [1]
Incubation of 10 μmol/L NVP-AUY922 with mouse and human liver microsomes for 30 min resulted in 69 ± 4% and 59 ± 15% metabolism (mean ± SE, n = 3), respectively, considerably less than the isoxazole VER-50589, which showed 71 ± 5% metabolism at 5 min and complete metabolism after 15 min of incubation (34). The main NVP-AUY922 metabolites measured in mouse plasma were the glucuronide of the parent, a deethylated product, and an oxidation product. The glucuronide represented ∼95% of plasma metabolites as estimated by their area under the curves following i.v. and i.p. administration. Plasma pharmacokinetic variables compared well with those described for other pyrazole and isoxazole HSP90 inhibitors (31, 34), with similar fast clearances following both i.p. and i.v. administration to athymic mice bearing WM266.4 human melanomas (Fig. 4A–D). However, as predicted from its decreased metabolism and high cellular uptake, NVP-AUY922 showed enhanced tissue distribution with ratios of ≥4.0 in WM266.4 tumors, liver, and spleen compared with plasma following i.v. administration. Importantly, tumor clearance was significantly lower than that of normal tissues, with a longer terminal half-life of 14.7 to 15.5 h. This resulted in tumor NVP-AUY922 levels at least 100 × GI50 concentrations over 24 h following both i.v. and i.p. administration. Similar pharmacokinetic profiles were observed in other human tumor xenografts as indicated below.

[1]. NVP-AUY922: A Novel Heat Shock Protein 90 Inhibitor Active against Xenograft Tumor Growth, Angiogenesis, and Metastasis. Cancer Research (2008), 68(8), 2850-2860.

[2]. Heat shock protein-90 inhibitor, NVP-AUY922, is effective in combination with NSC 118218 against chronic lymphocytic leukemia cells cultured on CD40L-stromal layer and inhibits their activated/proliferative phenotype. Leuk Lymphoma. 2012 J.

[3]. Stoeltzing O.Targeting HSP90 by the novel inhibitor NVP-AUY922 reduces growth and angiogenesis of pancreatic cancer. Anticancer Res. 2012 Jul;32(7):2551-61.

Luminespib Mesylate is the mesylate salt of luminespib, a derivative of 4,5-diarylisoxazole and a third-generation heat shock protein 90 (Hsp90) inhibitor with potential antineoplastic activity. Upon administration, luminespib binds with high affinity to and inhibits Hsp90, resulting in the proteasomal degradation of oncogenic client proteins; the inhibition of cell proliferation; and the elevation of heat shock protein 72 (Hsp72) in a wide range of human tumor cell lines. Hsp90, a 90 kDa molecular chaperone, plays a key role in the conformational maturation, stability and function of other substrate or "client" proteins within the cell, many of which are involved in signal transduction, cell cycle regulation and apoptosis, including kinases, transcription factors and hormone receptors. Hsp72 exhibits anti-apoptotic functions; its up-regulation may be used as a surrogate marker for Hsp90 inhibition.

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Luminespib is a monocarboxylic acid amide obtained by formal condensation of the carboxy group of 5-(2,4-dihydroxy-5-isopropylphenyl)-4-[4-(morpholin-4-ylmethyl)phenyl]-1,2-oxazole-3-carboxylic acid with the amino group of ethylamine. It has a role as a Hsp90 inhibitor, an antineoplastic agent and an angiogenesis inhibitor. It is a member of isoxazoles, a member of resorcinols, a member of morpholines, a monocarboxylic acid amide and an aromatic amide.
Luminespib is a derivative of 4,5-diarylisoxazole and a third-generation heat shock protein 90 (Hsp90) inhibitor with potential antineoplastic activity. Luminespib has been shown to bind with high affinity to and inhibit Hsp90, resulting in the proteasomal degradation of oncogenic client proteins; the inhibition of cell proliferation; and the elevation of heat shock protein 72 (Hsp72) in a wide range of human tumor cell lines. Hsp90, a 90 kDa molecular chaperone, plays a key role in the conformational maturation, stability and function of other substrate or "client" proteins within the cell, many of which are involved in signal transduction, cell cycle regulation and apoptosis, including kinases, transcription factors and hormone receptors. Hsp72 exhibits anti-apoptotic functions; its up-regulation may be used as a surrogate marker for Hsp90 inhibition.

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We describe the biological properties of NVP-AUY922, a novel resorcinylic isoxazole amide heat shock protein 90 (HSP90) inhibitor. NVP-AUY922 potently inhibits HSP90 (K(d) = 1.7 nmol/L) and proliferation of human tumor cells with GI(50) values of approximately 2 to 40 nmol/L, inducing G(1)-G(2) arrest and apoptosis. Activity is independent of NQO1/DT-diaphorase, maintained in drug-resistant cells and under hypoxic conditions. The molecular signature of HSP90 inhibition, comprising induced HSP72 and depleted client proteins, was readily demonstrable. NVP-AUY922 was glucuronidated less than previously described isoxazoles, yielding higher drug levels in human cancer cells and xenografts. Daily dosing of NVP-AUY922 (50 mg/kg i.p. or i.v.) to athymic mice generated peak tumor levels at least 100-fold above cellular GI(50). This produced statistically significant growth inhibition and/or regressions in human tumor xenografts with diverse oncogenic profiles: BT474 breast tumor treated/control, 21%; A2780 ovarian, 11%; U87MG glioblastoma, 7%; PC3 prostate, 37%; and WM266.4 melanoma, 31%. Therapeutic effects were concordant with changes in pharmacodynamic markers, including induction of HSP72 and depletion of ERBB2, CRAF, cyclin-dependent kinase 4, phospho-AKT/total AKT, and hypoxia-inducible factor-1alpha, determined by Western blot, electrochemiluminescent immunoassay, or immunohistochemistry. NVP-AUY922 also significantly inhibited tumor cell chemotaxis/invasion in vitro, WM266.4 melanoma lung metastases, and lymphatic metastases from orthotopically implanted PC3LN3 prostate carcinoma. NVP-AUY922 inhibited proliferation, chemomigration, and tubular differentiation of human endothelial cells and antiangiogenic activity was reflected in reduced microvessel density in tumor xenografts. Collectively, the data show that NVP-AUY922 is a potent, novel inhibitor of HSP90, acting via several processes (cytostasis, apoptosis, invasion, and angiogenesis) to inhibit tumor growth and metastasis. NVP-AUY922 has entered phase I clinical trials.[1]

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Chronic lymphocytic leukemia (CLL) involves disease infiltration into active proliferation centers within the lymph nodes and marrow. Successful treatment of CLL must involve targeting the leukemic cells in these supportive microenvironments. Our recent data suggest that inhibition of heat shock protein-90 (Hsp90) may be an effective treatment for CLL. We sought to further these data to determine whether the Hsp90 inhibitor, AUY922 (Novartis), is effective against CLL cells in a supportive in vitro environment. AUY922 significantly attenuated changes in immunophenotype and signal transducer and activator of transcription 3 (STAT3) signaling induced by CD40L-fibroblast co-culture but had no effect on the viability of CLL cells in this model. However, AUY922 in combination with fludarabine was significantly more effective at inducing apoptosis in cells in co-culture than either drug alone, an effect that was irrespective of ATM/TP53 dysfunction. In conclusion, our data suggest that further studies and clinical trials of AUY922 in combination with fludarabine may be warranted. [2]

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Aim: To evaluate the impact of heat-shock protein 90 (HSP90) blockade by the novel inhibitor NVP-AUY922, on tumor growth and angiogenesis in pancreatic cancer. Materials and methods: Effects of NVP-AUY922 on signaling pathways were evaluated by western blotting. Cell motility of cancer cells, pericytes and endothelial cells was investigated in Boyden chambers. Impact of HSP90 blockade on pancreatic tumor growth and angiogenesis were studied in in vivo tumor models. Results: NVP-AUY922 effectively inhibited cancer cell growth. Moreover, HSP90 inhibition potently interfered with multiple signaling pathways in cancer cells, as well as endothelial cells and pericytes, leading to significant reduction of pro-migratory and invasive properties of these cell types. In vivo, treatment with NVP-AUY922 significantly inhibited growth and vascularization of pancreatic cancer at doses far below the maximum tolerated dose. Conclusion: HSP90 blockade by the novel synthetic inhibitor NVP-AUY922 effectively reduces pancreatic cancer progression through direct effects on cancer cells, as well as on endothelial cells and pericytes.[3]

C27H37N3O9S

579.662386655808

579.225

C, 55.95; H, 6.43; N, 7.25; O, 24.84; S, 5.53

1051919-26-6

747412-49-3; 1051919-21-1 (mesylate) ; 747412-64-2 (HCl); 1051919-26-6 (mesylate hydrate)

135565012

Typically exists as solid at room temperature

3.744

5

11

7

40

743

0

S(C)(=O)(=O)O.O1CCN(CC2C=CC(=CC=2)C2C(C(NCC)=O)=NOC=2C2=C(C=C(C(=C2)C(C)C)O)O)CC1.O

TUURDQPZDIZCLK-UHFFFAOYSA-N

InChI=1S/C26H31N3O5.CH4O3S.H2O/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;1-5(2,3)4;/h5-8,13-14,16,30-31H,4,9-12,15H2,1-3H3,(H,27,32);1H3,(H,2,3,4);1H2

5-(2,4-dihydroxy-5-propan-2-ylphenyl)-N-ethyl-4-[4-(morpholin-4-ylmethyl)phenyl]-1,2-oxazole-3-carboxamide;methanesulfonic acid;hydrate

Luminespib mesylate; Luminespib mesylate hydrate; NVP-AUY922-AGB; Luminespib mesylate [USAN]; 1051919-26-6; UNII-6R0MAC137G; 6R0MAC137G; Luminespib mesylate (USAN);

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

May dissolve in DMSO (in most cases), if not, try other solvents such as H2O, Ethanol, or DMF with a minute amount of products to avoid loss of samples

Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.

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Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)
*Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution.
Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)
Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil)
Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals).

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Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)]
*Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.
Injection Formulation 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (i.e. 500 μL 2-Hydroxypropyl-β-cyclodextrin → 500 μL Saline)
Injection Formulation 6: DMSO : PEG300 : castor oil : Saline = 5 : 10 : 20 : 65 (i.e. 50 μL DMSO → 100 μLPEG300 → 200 μL castor oil → 650 μL Saline)
Injection Formulation 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (i.e. 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline)
Injection Formulation 8: Dissolve in Cremophor/Ethanol (50 : 50), then diluted by Saline
Injection Formulation 9: EtOH : Corn oil = 10 : 90 (i.e. 100 μL EtOH → 900 μL Corn oil)
Injection Formulation 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL EtOH → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)

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Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium)
Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose
Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals).

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Oral Formulation 3: Dissolved in PEG400
Oral Formulation 4: Suspend in 0.2% Carboxymethyl cellulose
Oral Formulation 5: Dissolve in 0.25% Tween 80 and 0.5% Carboxymethyl cellulose
Oral Formulation 6: Mixing with food powders

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Note: Please be aware that the above formulations are for reference only. InvivoChem strongly recommends customers to read literature methods/protocols carefully before determining which formulation you should use for in vivo studies, as different compounds have different solubility properties and have to be formulated differently.

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 (Please use freshly prepared in vivo formulations for optimal results.)