5-[2,4-dihydroxy-5-(propan-2-yl)phenyl]-N-ethyl-4-[4-(morpholin-4-ylmethyl)phenyl]-1,2-oxazole-3-carboxamide

• ChemBase编号: 72490
• 分子式: C26H31N3O5
• 平均质量: 465.54144
• 单一同位素质量: 465.22637111
• SMILES: c1(cc(c(cc1c1c(c(no1)C(=O)NCC)c1ccc(cc1)CN1CCOCC1)C(C)C)O)O
• Canonical SMILES: CCNC(=O)c1noc(c1c1ccc(cc1)CN1CCOCC1)c1cc(C(C)C)c(cc1O)O
• InChI: InChI=1S/C26H31N3O5/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/h5-8,13-14,16,30-31H,4,9-12,15H2,1-3H3,(H,27,32)
• InChIKey: NDAZATDQFDPQBD-UHFFFAOYSA-N

名称和登记号

名称

• IUPAC标准名: 5-[2,4-dihydroxy-5-(propan-2-yl)phenyl]-N-ethyl-4-[4-(morpholin-4-ylmethyl)phenyl]-1,2-oxazole-3-carboxamide
• IUPAC传统名: nvp-AUY922
• 别名: AUY922; VER-52296; NVP-AUY922

登记号

• CAS号: 747412-49-3
• PubChem SID: 162037415
• PubChem CID: 10096043

理论计算性质

• Acid pKa: 8.5101385
• 质子受体: 6
• 质子供体: 3
• LogD (pH = 5.5): 2.0758653
• LogD (pH = 7.4): 3.503119
• Log P: 3.5518167
• 摩尔折射率: 131.7714 cm^3
• 极化性: 52.099316 Å^3
• 极化表面积: 108.06 Å^2
• 可自由旋转的化学键: 7
• 里宾斯基五规则: true

分子性质

理化性质

• 溶解度: DMSO

安全信息

• 保存条件: -20°C

药理学性质

• 作用靶点: HSP

产品相关信息

• 成盐信息: Free Base

详细说明

Selleck Chemicals - S1069

Research Area

• Description: Cancer

Biological Activity

• Description: NVP-AUY922 (VER-52296) is a highly potent HSP90 inhibitor for HSP90α and HSP90β with IC50 of 13 nM and 21 nM, respectively.
• Targets: HSP90α; HSP90β
• IC50: 13 nM; 21 nM ^[1]
• In Vitro: NVP-AUY922 inhibits proliferation of various human cancer cell lines in vitro, with an average GI50 of 9 nM. ^[1] The IC50 values of NVP-AUY922 fall in the range of 2 to 40 nM in these gastric cancer cell lines. IC50 value for the BEAS-2B cells is 28.49 nM. Treatment with NVP-AUY922 does not influence the expression of HSP90, but expression of HSP70 gets elevated by NVP-AUY922 treatment. NVP-AUY922 increases the binding of HSP70 to HSP90. NVP-AUY922 causes p23 dissociation from the HSP90 complex and can then recruit HSP70 to the HSP90 complex.^[1] After the treatment with NVP-AUY922, expression of receptor tyrosine kinases including VEGFR1, 2, 3 and PDGFRɑ is decreased. A decrease is also noticed in the expression of Akt and phospho-Akt. Meanwhile, treatment with NVP-AUY922 causes decreased expression of HER-2 in NCI-N87 cells. NVP-AUY922 treatment results in binding of HSP90 to client proteins and setting them up as targets for degradation by the proteasome. NVP-AUY922 can influence cell growth by affecting mutiple signaling pathways. In addition, treatment with the proteasome inhibitor, MG132, restores expression of thymidylate synthase, which is decreased by NVP-AUY922. NVP-AUY922 increases the expression of cleaved caspase-3 leading to apoptosis in HSC-2 cells.^[1]
• In Vivo: Treatment with NVP-AUY922 causes a robust antitumor response and inhibits p-Akt and VEGF expression in an HSC-2 xenograft model. ^[2] Regressions are observed in 5 of 12 tumors. Body weight loss is <5% and="" clear="" biomarker="" changes="" consistent="" with="" hsp90="" inhibition="" are="" obtained="" in="" both="" studies="" (supplementary="" fig.="" s5c="" and="" d).="" in="" bt474,="" complete="" loss="" of="" erbb2="" and="" substantial="" depletion="" of="" erα="" are="" shown,="" in="" addition="" to="" reductions="" in="" cdk4="" and="" phospho-erk1/2.="">^[3]

Protocol

• Protocol: Kinase Assay ^[3]
• Kinase assay: NVP-AUY922 is dissolved in DMSO at a concentration of 10 mM. NVP-AUY922 is assessed against HSP90α, HSP90β, GRP94, TRAP-1, HSP72, and topoisomerase II. Profiling against a panel of kinases has been carried out and screening against a panel of additional enzymes and receptors is performed at Cerep.
• Protocol: Cell Assay ^[1]
• Cell Lines: Human gastric cancer cells NCI-N87
• Concentrations: 1 μM
• Incubation Time: 3 days
• Methods: Human gastric cancer cells NCI-N87 (5-7 ×10^3 in 50 μL/well) are seeded in 96-well plates and incubated at 37 °C for 24 hours, followed by NVP-AUY922 treatment for 1-3 days at 37 °C. After treatment, the cells are assayed by MTT method and analyzed by microplate reader.
• Protocol: Animal Study ^[3]
• Animal Models: Female NCr athymic mice bearing WM266.4 human melanoma xenografts
• Formulation: In DMSO and diluted in sterile saline/Tween 20
• Doses: 50 mg/kg
• Administration: Administered via i.v. or i.p.

References

• References: [1] Lee KH, et al. Cancer Sci, 2011, 102(7), 1388-1395.
• References: [2] Okui T, et al. Anticancer Res, 2011, 31(4), 1197-1204.
• References: [3] Eccles SA, et al. Cancer Res, 2008, 68(8), 2850-2860.

参考文献

• Lee KH, et al. Cancer Sci, 2011, 102(7), 1388-1395.
• Okui T, et al. Anticancer Res, 2011, 31(4), 1197-1204.
• Eccles SA, et al. Cancer Res, 2008, 68(8), 2850-2860.