PF-04929113 (SNX-5422)

PF-04929113(SNX-5422)は、41nMのKdによる強力で選択的なHsp90阻害剤で、そのうえ37nMのIC50で、Her-2退廃を妨げます。

目録号S2656
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PF-04929113 (SNX-5422) 化学構造
分子量: 521.53

品質と確認

Quality Control & MSDS

製品情報

製品の説明

生物活性

情報 PF-04929113(SNX-5422)は、41nMのKdによる強力で選択的なHsp90阻害剤で、そのうえ37nMのIC50で、Her-2退廃を妨げます。
目標 HSP90 Her-2
IC50 41 nM (Kd) 37 nM [1]
In vitro試験 PF-04929113 is a small-molecule Hsp90 inhibitor based on the 6,7-dihydro-indazol-4-one scaffold. PF-04929113 developed by Serenex, converts to SNX-2122, which is the active Hsp90 inhibitor form. PF-04929113 exhibits potent effects on Her-2 stability and causes expected up-regulation of Hsp70. PF-04929113 shows potent antiproliferative activity against a broad range of cancer cell types, e.g. MCF-7 (IC50=16 nM), SW620 (IC50=19 nM), K562 (IC50=23 nM), SK-MEL-5 (IC50=25 nM), and A375 (IC50=51 nM). [1]
In vivo試験 PF-04929113 inhibits human MM cell growth in vivo, and immuno-histochemical analysis shows PF-04929113 significantly inhibits p-ERK and p-Akt in treated mice. Meanwhile, PF-04929113 treatment significantly decreases the percentage of CD31+ cells and MVD, consistent with an inhibitory effect on angiogenesis in vivo. A 50 mg/kg administration of PF-04929113 delivered 3 times per week significantly delays castrate-resistant LNCaP tumor growth and prolongs cancer specific survival. [2] Immuno-histochemical analysis indicates increased SP70 expression, and decreases Ki67, Akt, and AR expression, after treatment with PF-04929113. Inhibition of tumor progression by PF-04929113 may result from a combination of decreased proliferative (reduced Ki67 and Akt expression) or increased apoptosis (increased ApopTag staining) rates. [3]
臨床試験 PF-04929113 is currently under the Phase I clinical trial for the safety and pharmacology study in subjects with refractory solid tumor malignancies.
特集

推薦された実験操作 (公開の文献だけ)

キナーゼアッセイ: [1]

Affinity for Hsp90 Hsp90 from porcine spleen extract is isolated by affinity capture on a purine-affinity media. The Hsp90 loaded media is then 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.

細胞アッセイ: [1]

細胞系 MCF-7, SW620, K562, SK-MEL-5 and A375 cancer cell lines
濃度 0-300 nM
処理時間 72 or 144 hours
方法 All assays are done in 96-well plates. All cell lines are purchased from ATCC. 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 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.

動物実験: [2]

動物モデル 5 × 106 MM.1S cells are inoculated subcutaneously in the Fox Chase SCID mice (6-7 weeks old).
製剤 PF-04929113 is dissolved in 1% carboxy methylcellulose/0.5% Tween 80 at 10 mg/mL and stored at 4 °C for in vivo stud
投薬量 20 or 40 mg/kg
管理 PF-04929113 is administered orally 3 times per week, total 3 weeks.
1

参考

化学情報

Download PF-04929113 (SNX-5422) SDF
分子量 521.53
化学式

C25H30F3N5O4

CAS No. 908115-27-5
別名 N/A
溶解度 (25°C)
  • DMSO 104 mg/mL
  • 水 <1 mg/mL
  • エタノール 5 mg/mL
保管 2年 -20°C
6月-80°Cin DMSO
化学名 (1r,4r)-4-(2-carbamoyl-5-(6,6-dimethyl-4-oxo-3-(trifluoromethyl)-4,5,6,7-tetrahydroindazol-1-yl)phenylamino)cyclohexyl 2-aminoacetate

研究分野

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