| 名稱 | PF04929113 |
| 描述 | PF04929113 (SNX-5422) is a synthetic, novel, small molecule Hsp90 Inhibitor. As an oral formulation that demonstrates strong efficacy and tolerability, PF04929113 is positioned as a breakthrough therapy with broad applicability across a wide range of cancers. |
| 細胞實驗 | Cell lines: MCF-7,SW620,K562,SK-MEL-5 and A375 cancer cell lines. Concentrations: 0-300 nM. Method: Proliferation rates are measured by seeding cells into 96-well plates,followed by compound addition 24 h later.After addition of PF-04929113,cells are allowed to grow for either an additional 72 or 144 h depending on the rate of growth.At harvest,media is removed and DNA content for individual wells is determined using CyQuant DNA dye.Levels of Hsp90 client proteins and phosphor-regulated proteins in A375 are measured by high content analysis (HCA) using an ArrayScan 4.5 instrument after 24 hours of treatment with PF-04929113,followed by methanol fixation.After fixation in 4% PBS-buffered formalin and permeablization with 0.1% TX-100,cells are probed with anti-Her2,antiphospho-S6 (pS6),antipERK,and anti-Hsp70 primary antibodies,followed by TRITC or FITC conjugated secondary antibodies.Nuclei are also stained with Hoechst DNA binding dye.For each well,250-500 individual nuclei are identified along with the average staining intensity for the client and phospho-proteins for each cell.Average client staining intensities are then calculated for each well. |
| 激酶實驗 | The Hsp90 loaded media is challenged with PF-04929113 at a given concentration, ranging from 0.8 to 500 μM, and the amount of Hsp90 liberated at each concentration is determined by Bradford protein assay. The resulting IC50 values are corrected for the ATP ligand concentration and presented as apparent Kd values. |
| 動物實驗 | Animal Models: 5 ×106 MM.1S cells are inoculated subcutaneously in the Fox Chase SCID mice (6-7 weeks old). Formulation: PF-04929113 is dissolved in 1% carboxy methylcellulose/0.5% Tween 80 at 10 mg/mL and stored at 4 °C. Dosages: 20 or 40 mg/kg. Administration: orally 3 times per week,3 weeks in total. |
| 體外活性 | 免疫組織化學分析表明,在用PF-04929113處理后,SP70表達增加,并降低Ki67,Akt和AR表達.PF-04929113在體內(nèi)抑制人類MM細胞生長,并且免疫組織化學分析顯示PF-04929113顯著抑制處理的小鼠中的p-ERK和p-Akt.同時,PF-04929113處理顯著降低CD31+細胞和MVD百分比,與體內(nèi)血管生成的抑制作用一致.PF-04929113對腫瘤發(fā)展的抑制可能由增殖減少（Ki67和Akt表達降低）或凋亡率增加（增加的ApopTag染色）共同引起. |
| 體內(nèi)活性 | PF-04929113對Her-2穩(wěn)定性表現(xiàn)出有效的作用并導致預期的Hsp70上調(diào)。PF-04929113顯示針對廣泛癌癥細胞類型的有效抗增殖活性,例如,MCF-7（IC50 = 16 nM）,SW620（IC50 = 19 nM）,K562（IC50 = 23 nM）,SK-MEL-5（IC50 = 25 nM）和A375（IC50 = 51 nM）。 |
| 存儲條件 | Powder: -20°C for 3 years | In solvent: -80°C for 1 year
Shipping with blue ice/Shipping at ambient temperature. |
| 溶解度 | 10% DMSO+40% PEG300+5% Tween 80+45% Saline : 10 mg/mL (19.17 mM), Solution.
H2O : < 1 mg/mL (insoluble or slightly soluble)
Ethanol : 3 mg/mL (5.75 mM), Sonication is recommended.
DMSO : 120 mg/mL (230.09 mM), Sonication is recommended.
10% DMSO+90% Saline : < 10 mg/mL (19.17 mM), Lower concentrations may be soluble, but exact solubility limit is unknown.
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| 關鍵字 | SNX5422 | SNX 5422 | PF04929113 | HSP90 | HER2 |
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