VER-50589HSP90 inhibitor, potent CAS# 747413-08-7 |
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Quality Control & MSDS
3D structure
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| Cas No. | 747413-08-7 | SDF | Download SDF |
| PubChem ID | 16058668 | Appearance | Powder |
| Formula | C19H17ClN2O5 | M.Wt | 388.8 |
| Type of Compound | N/A | Storage | Desiccate at -20°C |
| Solubility | DMSO : ≥ 48 mg/mL (123.46 mM) *"≥" means soluble, but saturation unknown. | ||
| Chemical Name | (5Z)-5-(3-chloro-4-hydroxy-6-oxocyclohexa-2,4-dien-1-ylidene)-N-ethyl-4-(4-methoxyphenyl)-2H-1,2-oxazole-3-carboxamide | ||
| SMILES | CCNC(=O)C1=C(C(=C2C=C(C(=CC2=O)O)Cl)ON1)C3=CC=C(C=C3)OC | ||
| Standard InChIKey | DGNFSLDDDQFHNU-PDGQHHTCSA-N | ||
| Standard InChI | InChI=1S/C19H17ClN2O5/c1-3-21-19(25)17-16(10-4-6-11(26-2)7-5-10)18(27-22-17)12-8-13(20)15(24)9-14(12)23/h4-9,22,24H,3H2,1-2H3,(H,21,25)/b18-12- | ||
| 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. |
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| 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. |
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| 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. | ||
| Description | VER-50589 is a potent inhibitor of HSP90 with IC50 value of 21 nM for HSP90β. | |||||
| Targets | HSP90β | |||||
| IC50 | 21 nM | |||||
VER-50589 Dilution Calculator
VER-50589 Molarity Calculator
| 1 mg | 5 mg | 10 mg | 20 mg | 25 mg | |
| 1 mM | 2.572 mL | 12.8601 mL | 25.7202 mL | 51.4403 mL | 64.3004 mL |
| 5 mM | 0.5144 mL | 2.572 mL | 5.144 mL | 10.2881 mL | 12.8601 mL |
| 10 mM | 0.2572 mL | 1.286 mL | 2.572 mL | 5.144 mL | 6.43 mL |
| 50 mM | 0.0514 mL | 0.2572 mL | 0.5144 mL | 1.0288 mL | 1.286 mL |
| 100 mM | 0.0257 mL | 0.1286 mL | 0.2572 mL | 0.5144 mL | 0.643 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. | |||||
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VER-50589 is a potent inhibitor of HSP90 with IC50 value of 21 nM for HSP90β [1].
Heat shock protein 90 (HSP90) is a chaperone protein that stabilizes proteins against heat stress, assists proteins to fold properly and aids in protein degradation. Also, HSP90 stabilizes proteins required for tumor growth.
VER-50589 is a potent HSP90 inhibitor. VER-50589 inhibited recombinant yeast Hsp90 ATPase activity with IC50 value of 143 nM at 400 μM ATP and inhibited recombinant human HSP90β with IC50 value of 821 nM in the presence of the activator AHA1. Also, VER-50589 bound to recombinant human HSP90β with Kd value of 4.5 nM. In human cancer cells, VER-50589 exhibited antiproliferative activity with mean GI50 value of 78 nM. In CH1 human ovarian cells, VER-50589 inhibited cell growth with GI50 value of 32.7 nM. In HT29 cells, VER-50589 exhibited extensive glucuronidation and increased glucuronide levels by 50-fold, which were responsible for the resistance. In CH1doxR cells that were resistant to doxorubicin, VER-50589 exhibited similar cellular GI50 value compared with CH1 cells. In HCT116 colon cancer cells, VER-50589 caused G1 and G2-M block. Also, VER-50589 induced cytostasis and apoptosis [1].
In athymic mice bearing OVCAR3 human ovarian ascites tumors, VER-50589 completely inhibited HSP90. In mice bearing HCT116 colon carcinoma xenografts, VER-50589 (100 mg/kg) reduced tumor volume by 30% and tumor weight by 26%. Also, VER-50589 reduced expression of ERBB2 and C-RAF [1].
Reference:
[1]. Sharp SY, Prodromou C, Boxall K, et al. Inhibition of the heat shock protein 90 molecular chaperone in vitro and in vivo by novel, synthetic, potent resorcinylic pyrazole/isoxazole amide analogues. Mol Cancer Ther, 2007, 6(4): 1198-1211.
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Acquired resistance to 17-allylamino-17-demethoxygeldanamycin (17-AAG, tanespimycin) in glioblastoma cells.[Pubmed:19244114]
Cancer Res. 2009 Mar 1;69(5):1966-75.
Heat shock protein 90 (HSP90) inhibitors, such as 17-allylamino-17-demethoxygeldanamycin (17-AAG, tanespimycin), which is currently in phase II/phase III clinical trials, are promising new anticancer agents. Here, we explored acquired resistance to HSP90 inhibitors in glioblastoma (GB), a primary brain tumor with poor prognosis. GB cells were exposed continuously to increased 17-AAG concentrations. Four 17-AAG-resistant GB cell lines were generated. High-resistance levels with resistance indices (RI = resistant line IC(50)/parental line IC(50)) of 20 to 137 were obtained rapidly (2-8 weeks). After cessation of 17-AAG exposure, RI decreased and then stabilized. Cross-resistance was found with other ansamycin benzoquinones but not with the structurally unrelated HSP90 inhibitors, radicicol, the purine BIIB021, and the resorcinylic pyrazole/isoxazole amide compounds VER-49009, VER-50589, and NVP-AUY922. An inverse correlation between NAD(P)H/quinone oxidoreductase 1 (NQO1) expression/activity and 17-AAG IC(50) was observed in the resistant lines. The NQO1 inhibitor ES936 abrogated the differential effects of 17-AAG sensitivity between the parental and resistant lines. NQO1 mRNA levels and NQO1 DNA polymorphism analysis indicated different underlying mechanisms: reduced expression and selection of the inactive NQO1*2 polymorphism. Decreased NQO1 expression was also observed in a melanoma line with acquired resistance to 17-AAG. No resistance was generated with VER-50589 and NVP-AUY922. In conclusion, low NQO1 activity is a likely mechanism of acquired resistance to 17-AAG in GB, melanoma, and, possibly, other tumor types. Such resistance can be overcome with novel HSP90 inhibitors.
Inhibition of the heat shock protein 90 molecular chaperone in vitro and in vivo by novel, synthetic, potent resorcinylic pyrazole/isoxazole amide analogues.[Pubmed:17431102]
Mol Cancer Ther. 2007 Apr;6(4):1198-211.
Although the heat shock protein 90 (HSP90) inhibitor 17-allylamino-17-demethoxygeldanamycin (17-AAG) shows clinical promise, potential limitations encourage development of alternative chemotypes. We discovered the 3,4-diarylpyrazole resorcinol CCT018159 by high-throughput screening and used structure-based design to generate more potent pyrazole amide analogues, exemplified by VER-49009. Here, we describe the detailed biological properties of VER-49009 and the corresponding isoxazole VER-50589. X-ray crystallography showed a virtually identical HSP90 binding mode. However, the dissociation constant (K(d)) of VER-50589 was 4.5 +/- 2.2 nmol/L compared with 78.0 +/- 10.4 nmol/L for VER-49009, attributable to higher enthalpy for VER-50589 binding. A competitive binding assay gave a lower IC(50) of 21 +/- 4 nmol/L for VER-50589 compared with 47 +/- 9 nmol/L for VER-49009. Cellular uptake of VER-50589 was 4-fold greater than for VER-49009. Mean cellular antiproliferative GI(50) values for VER-50589 and VER-49009 for a human cancer cell line panel were 78 +/- 15 and 685 +/- 119 nmol/L, respectively, showing a 9-fold potency gain for the isoxazole. Unlike 17-AAG, but as with CCT018159, cellular potency of these analogues was independent of NAD(P)H:quinone oxidoreductase 1/DT-diaphorase and P-glycoprotein expression. Consistent with HSP90 inhibition, VER-50589 and VER-49009 caused induction of HSP72 and HSP27 alongside depletion of client proteins, including C-RAF, B-RAF, and survivin, and the protein arginine methyltransferase PRMT5. Both caused cell cycle arrest and apoptosis. Extent and duration of pharmacodynamic changes in an orthotopic human ovarian carcinoma model confirmed the superiority of VER-50589 over VER-49009. VER-50589 accumulated in HCT116 human colon cancer xenografts at levels above the cellular GI(50) for 24 h, resulting in 30% growth inhibition. The results indicate the therapeutic potential of the resorcinylic pyrazole/isoxazole amide analogues as HSP90 inhibitors.
