VER-49009HSP90 inhibitor, potent and selective CAS# 558640-51-0 |
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Quality Control & MSDS
3D structure
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| Cas No. | 558640-51-0 | SDF | Download SDF |
| PubChem ID | 5327095 | Appearance | Powder |
| Formula | C19H18ClN3O4 | M.Wt | 387.82 |
| Type of Compound | N/A | Storage | Desiccate at -20°C |
| Synonyms | CCT 129397 | ||
| Solubility | DMSO : 100 mg/mL (257.85 mM; Need ultrasonic) H2O : < 0.1 mg/mL (insoluble) | ||
| Chemical Name | (5Z)-5-(3-chloro-4-hydroxy-6-oxocyclohexa-2,4-dien-1-ylidene)-N-ethyl-4-(4-methoxyphenyl)-1,2-dihydropyrazole-3-carboxamide | ||
| SMILES | CCNC(=O)C1=C(C(=C2C=C(C(=CC2=O)O)Cl)NN1)C3=CC=C(C=C3)OC | ||
| Standard InChIKey | OLVDDJOCKKMKPE-ATVHPVEESA-N | ||
| Standard InChI | InChI=1S/C19H18ClN3O4/c1-3-21-19(26)18-16(10-4-6-11(27-2)7-5-10)17(22-23-18)12-8-13(20)15(25)9-14(12)24/h4-9,22-23,25H,3H2,1-2H3,(H,21,26)/b17-12- | ||
| 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-49009 is a Hsp90 inhibitor, with an IC50 of 25 nM and a Kd of 78 nM.In Vitro:VER-49009 is a Hsp90 inhibitor, with an IC50 of 25 nM. VER-49009 binds to the ATPase of full length yeast Hsp90 protein, with an IC50 of 140 nM[1]. VER-49009 inhibits Hsp90, with a Kd of 78 nM. VER-49009 also shows antiproliferative activities against various human cancer cells, with a mean GI50 of 685 ± 119 nM. VER-49009 suppressses the proliferation of human umbilical vein endothelial cells (HUVEC) with GI50 values of 444 ± 91.1 nM, and shows higher GI50s against nontumorigenic human breast (MCF10a) and prostate (PNT2) epithelial cells. VER-49009 displays no differences in cellular activities of isogenic cell lines, and these activities are independent of NQO1 expression[2]. VER-49009 inhibits the proliferation (1, 2.5 μM), induces G2 phase arrest and reduces total Akt and phospho-Akt expression levels in CFSC cells (1-5 μM)[3].In Vivo:VER-49009 (4 mg/kg, i.p.) results in clear depletion of ERBB2 at 3 and 8 h following the final dose, with client protein levels returning to normal by 24 h, in the athymic mice bearing well-established OVCAR3 human ovarian ascites tumors[2]. References: | |||||
VER-49009 Dilution Calculator
VER-49009 Molarity Calculator
| 1 mg | 5 mg | 10 mg | 20 mg | 25 mg | |
| 1 mM | 2.5785 mL | 12.8926 mL | 25.7852 mL | 51.5703 mL | 64.4629 mL |
| 5 mM | 0.5157 mL | 2.5785 mL | 5.157 mL | 10.3141 mL | 12.8926 mL |
| 10 mM | 0.2579 mL | 1.2893 mL | 2.5785 mL | 5.157 mL | 6.4463 mL |
| 50 mM | 0.0516 mL | 0.2579 mL | 0.5157 mL | 1.0314 mL | 1.2893 mL |
| 100 mM | 0.0258 mL | 0.1289 mL | 0.2579 mL | 0.5157 mL | 0.6446 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-49009 is a potent and selective inhibitor of HSP90 with IC50 value of 47 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-49009 is a potent HSP90 inhibitor. VER-49009 inhibited recombinant yeast Hsp90 ATPase activity with IC50 value of 167 nM at 400 μM ATP and inhibited recombinant human HSP90β with IC50 value of 1033 nM in the presence of the activator AHA1. Also, VER-49009 bound to recombinant human HSP90β with Kd value of 78.0 nM. In human cancer cells, VER-49009 exhibited antiproliferative activity with mean GI50 value of 685 nM. In HT29 cells, VER-49009 exhibited extensive glucuronidation and increased glucuronide levels by 230-fold, which were responsible for the resistance. In CH1doxR cells that were resistant to doxorubicin, VER-49009 exhibited similar cellular GI50 value compared with CH1 cells. In HCT116 colon cancer cells, VER-49009 caused G1 and G2-M block [1].
In athymic mice bearing OVCAR3 human ovarian ascites tumors, VER-49009 completely inhibited ERBB2 [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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Discovery of hybrid Hsp90 inhibitors and their anti-neoplastic effects against gefitinib-resistant non-small cell lung cancer (NSCLC).[Pubmed:24345447]
Bioorg Med Chem Lett. 2014 Jan 1;24(1):224-7.
Heat shock protein 90 (Hsp90) represents an attractive cancer therapeutic target due to its role in the stabilization and maturation of many oncogenic proteins. We have designed a series of hybrid Hsp90 inhibitors by connecting the resorcinol ring of VER-49009 (2) and the trimethoxyphenyl ring of PU3 (3) using structure-based approach. Subsequent testing established that compound 1f inhibited gefitinib-resistant H1975 cell proliferation, brought about the degradation of Hsp90 client proteins including EGFR, Met, Her2 and Akt and induced the expression of Hsp70. The design, synthesis, and evaluation of 1f are described herein.
Inhibition of hepatic stellate cell proliferation by heat shock protein 90 inhibitors in vitro.[Pubmed:19412730]
Mol Cell Biochem. 2009 Oct;330(1-2):181-5.
Hepatic stellate cells (HSCs) play an important role in the development of hepatic fibrosis. Heat shock protein 90 (Hsp90) is essential for the maturation and activity of a varied group of proteins involved in signal transduction and cell cycle regulation. In this study, we found that two Hsp90 inhibitors, VER-49009 and its analog VER-49009M, inhibited the proliferation of hepatic stellate cell line CFSC cells, and both of them induced G2 phase arrest in CFSC cells. Akt expression was decreased by the treatment of Hsp90 inhibitors in CFSC cells. Based on these findings, we propose that the inhibition of Hsp90 might be a rational approach in the prevention of liver fibrosis.
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.
4-Amino derivatives of the Hsp90 inhibitor CCT018159.[Pubmed:16480864]
Bioorg Med Chem Lett. 2006 May 1;16(9):2543-8.
Novel piperazinyl, morpholino and piperidyl derivatives of the pyrazole-based Hsp90 inhibitor CCT018159 are described. Structure-activity relationships have been elucidated by X-ray co-crystal analysis of the new compounds bound to the N-terminal domain of human Hsp90. Key features of the binding mode are essentially identical to the recently reported potent analogue VER-49009. The most potent of the new compounds has a methylsulfonylbenzyl substituent appended to the piperazine nitrogen, possesses an IC50 of less than 600 nM binding against the enzyme and demonstrates low micromolar inhibition of tumour cell proliferation.
Novel, potent small-molecule inhibitors of the molecular chaperone Hsp90 discovered through structure-based design.[Pubmed:15974572]
J Med Chem. 2005 Jun 30;48(13):4212-5.
The crystal structure of a previously reported screening hit 1 (CCT018159) bound to the N terminal domain of molecular chaperone Hsp90 has been used to design 5-amide analogues. These exhibit enhanced potency against the target in binding and functional assays with accompanying appropriate cellular pharmacodynamic changes. Compound 11 (VER-49009) compares favorably with the clinically evaluated 17-AAG.
