中文名 | SNX-2112 (PF-04928473) |
英文名 | SNX-2112 (PF-04928473) |
别名 | 化合物SNX2112 HSP90抑制剂(SNX-2112) 2-[(反式-4-羟基环己基)氨基]-4-[4,5,6,7-四氢-6,6-二甲基-4-氧代-3-(三氟甲基)-1H-吲唑-1-基]苯甲酰胺 |
英文别名 | SNX-2112 PF 04928473 SNX-2112 (PF-04928473) 4-(6,6-Dimethyl-4-oxo-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl)-2-((1r,4r)-4-hyd 4-(6,6-dimethyl-4-oxo-3-(trifluoromethyl)-4,5,6,7-tetrahydroindazol-1-yl)-2-((1r,4r)-4-hydroxycyclohexylamino)benzamide 4-(6,6-dimethyl-4-oxo-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl)-2-((1r,4r)-4-hydroxycyclohexylamino)benzamide 2-[(trans-4-Hydroxycyclohexyl)amino]-4-[4,5,6,7-tetrahydro-6,6-dimethyl-4-oxo-3-(trifluoromethyl)-1H-indazol-1-yl]benzamide 4-(6,6-DIMETHYL-4-OXO-3-(TRIFLUOROMETHYL)-4,5,6,7-TETRAHYDRO-1H-INDAZOL-1-YL)-2-((1R,4R)-4-HYDROXYCYCLOHEXYLAMINO)BENZAMIDE SNX-2112 4-(6,6-DIMETHYL-4-OXO-3-(TRIFLUOROMETHYL)-4,5,6,7-TETRAHYDRO-1H-INDAZOL-1-YL)-2-((1R,4R)-4-HYDROXYCYCLOHEXYLAMINO)BENZAMIDE |
CAS | 908112-43-6 |
化学式 | C23H27F3N4O3 |
分子量 | 464.48 |
密度 | 1.47 |
熔点 | 265-266℃ |
溶解度 | DMSO: 25毫克/毫升 (53.82毫米; 需要超声波) |
存储条件 | -20℃ |
体外研究 | 使用1 μmol/L SNX-2112处理BT-474 细胞,在处理3到6小时期间,导致HER2表达下调,而处理10小时,则导致HER2表达几乎完全丧失。SNX-2112处理,也导致全部Akt表达降低。SNX-2112作用于BT474, SKBR-3, SKOV-3, MDA-468, MCF-7 和 H1650癌细胞,抑制细胞增殖,IC50为10 到 50 nM。这些抗增殖作用与Rb的低磷酸化, G1期停滞,和凋亡的适度调节水平相关。 SNX-2112竞争性结合到Hsp90的N-末端ATP结合位点。SNX-2112通过caspase-8, -9,-3,和PARP裂解而诱导凋亡。SNX-2112抑制生长因子诱导的Akt和细胞外信号相关激酶(ERK)激活,也克服白细胞介素(IL-6), 胰岛素样生长因子-1,和骨髓基质细胞诱导的生长优势。SNX-2112 通过废除eNOS/Akt通路而抑制人脐静脉内皮细胞管形成,也通过下调 ERK/c-fos 和PU.1而显著抑制破骨细胞形成。 研究细胞系(8种来自骨肉瘤,神经母细胞瘤,肝母细胞瘤,和淋巴瘤的细胞系)对SNX-2112的敏感性,IC50为10-100 nM。高剂量 (70 nM) 导致抑制时间更长,sub-G1累积更多。观察到随着PARP 裂解增多,AKT1和C-Raf 的水平显著降低。最新研究显示 NX-2112通过抑制Akt/mTOR/p70S6K而诱导自噬,这种作用存在时间和剂量依赖性。SNX-2112作用于人类黑色素瘤A-375细胞,显著诱导凋亡和自噬,说明 SNX-2112 可作为一种有效的靶向治疗剂。 |
体内研究 | SNX-2112是SNX-5422的药物前体,SNX-5422抑制MM细胞生长,延长移植瘤小鼠模型寿命,且抑制Hsp90,而SNX-2112不抑制MM细胞生长,但是在骨髓微环境中起作用而阻断血管生长和破骨细胞形成。 |
参考资料 展开查看 | 1: Liu KS, Liu H, Qi JH, Liu QY, Liu Z, Xia M, Xing GW, Wang SX, Wang YF. SNX-2112, an Hsp90 inhibitor, induces apoptosis and autophagy via degradation of Hsp90 client proteins in human melanoma A-375 cells. Cancer Lett. 2011 Dec 17. [Epub ahead of print] PubMed PMID: 22182451. 2: Wang SX, Ju HQ, Liu KS, Zhang JX, Wang X, Xiang YF, Wang R, Liu JY, Liu QY, Xia M, Xing GW, Liu Z, Wang YF. SNX-2112, a novel Hsp90 inhibitor, induces G2/M cell cycle arrest and apoptosis in MCF-7 cells. Biosci Biotechnol Biochem. 2011;75(8):1540-5. Epub 2011 Aug 7. PubMed PMID: 21821931. 3: Chinn DC, Holland WS, Yoon JM, Zwerdling T, Mack PC. Anti-tumor activity of the HSP90 inhibitor SNX-2112 in pediatric cancer cell lines. Pediatr Blood Cancer. 2011 Jul 27. doi: 10.1002/pbc.23270. [Epub ahead of print] PubMed PMID: 21796766. 4: Zhai QQ, Gong GQ, Liu Z, Luo Y, Xia M, Xing GW, You XF, Wang YF. Preclinical pharmacokinetic analysis of SNX-2112, a novel Hsp90 inhibitor, in rats. Biomed Pharmacother. 2011 Mar;65(2):132-6. Epub 2010 Dec 30. PubMed PMID: 21227627. 5: Bachleitner-Hofmann T, Sun MY, Chen CT, Liska D, Zeng Z, Viale A, Olshen AB, Mittlboeck M, Christensen JG, Rosen N, Solit DB, Weiser MR. Antitumor activity of SNX-2112, a synthetic heat shock protein-90 inhibitor, in MET-amplified tumor cells with or without resistance to selective MET Inhibition. Clin Cancer Res. 2011 Jan 1;17(1):122-33. PubMed PMID: 21208906; PubMed Central PMCID: PMC3263825. |
1mg | 5mg | 10mg | |
---|---|---|---|
1 mM | 2.153 ml | 10.765 ml | 21.529 ml |
5 mM | 0.431 ml | 2.153 ml | 4.306 ml |
10 mM | 0.215 ml | 1.076 ml | 2.153 ml |
5 mM | 0.043 ml | 0.215 ml | 0.431 ml |
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