product name PF-04929113 (SNX-5422)
Description: PF-04929113 (also known as SNX-5422), is a potent and selective HSP90 inhibitor with Kd of 41 nM and induces Her-2 degradation with IC50 of 37 nM. PF-04929113 is a synthetic prodrug of SNX-2112 with potential antineoplastic activity. PF-04929113 is rapidly converted to SNX-2112, which accumulates in tumors relative to normal tissues. SNX-2112 inhibits Hsp90, which may result in the proteasomal degradation of oncogenic client proteins, including HER2/ERBB2, and the inhibition of tumor cell proliferation.
References: J Med Chem. 2009;52(14):4288-305; Blood. 2009;113(4):846-55; Clin Cancer Res. 2011;17(8):2301-13.
521.53
Formula
C25H30F3N5O4
CAS No.
908115-27-5
Storage
-20℃ for 3 years in powder form
-80℃ for 2 years in solvent
Solubility (In vitro)
DMSO: 5 mg/mL (9.6 mM)
Water: <1 mg/mL
Ethanol: 3 mg/mL (5.2 mM)
Solubility (In vivo)
0.5% CMC+0.25% Tween 80: 25mg/mL
Synonyms
SNX-5422
other peoduct :
| In Vitro |
In vitro activity: 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). Kinase Assay: 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. Cell Assay: All assays are done in 96-well plates. All cell lines are purchased from ATCC. Proliferation rates are measured by seeding cells (MCF-7, SW620, K562, SK-MEL-5 and A375 cancer cell lines) 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. |
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| In Vivo | 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. 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. |
| Animal model | Fox Chase SCID mice bearing MM.1S cells |
| Formulation & Dosage | Dissolved in 1% carboxy methylcellulose/0.5% Tween 80 at 10 mg/mL and stored at 4 °C for in vivo study; 20 or 40 mg/kg; oral gavage |
| References | J Med Chem. 2009 Jul 23;52(14):4288-305; Blood. 2009 Jan 22;113(4):846-55; Clin Cancer Res. 2011 Apr 15;17(8):2301-13. |
