| Size | Price | Stock | Qty |
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| 5mg |
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| 10mg |
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| 25mg |
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| 50mg |
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| 100mg |
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| Other Sizes |
Purity: ≥98%
| Targets |
PF-04929113 mesylate (CAS#: 1173111-67-5) is a prodrug that rapidly converts to SNX-2112 (9), which targets Hsp90. The binding affinity (Kd) of the active form (SNX-2112) for Hsp90 is 41 nM (from Table 4, compound 10 entry, Kd value). [1]
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| ln Vitro |
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| ln 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. In an HT-29 human colon tumor xenograft model, oral administration of PF-04929113 mesylate (CAS#: 1173111-67-5) at 50 mg/kg (MWF schedule for 3 weeks) resulted in 67% tumor growth delay over vehicle control. Median time to endpoint for the 50 mg/kg group was 43.2 days compared to 25.9 days for vehicle control. Two of 10 animals survived to the end of the study (61 days). The compound was well tolerated at all dose levels tested (5, 10, 25, 50 mg/kg), with no treatment-related deaths observed. [1] |
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| Enzyme Assay |
The affinity of the active compound (SNX-2112, 9) for Hsp90 was determined as previously described. Briefly, Hsp90 from porcine spleen extract was isolated by affinity capture on a purine-affinity media. The Hsp90-loaded media was then challenged with test compound at concentrations ranging from 0.8 to 500 μM, and the amount of Hsp90 liberated at each concentration was determined by Bradford protein assay. The resulting IC50 values were corrected for the ATP ligand concentration and presented as apparent Kd values. The Kd for compound 9 was 41 nM. [1]
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| Cell Assay |
Cell proliferation assays: Cells were seeded into 96-well plates, and compound was added 24 h later. After 72 or 144 h of growth, media was removed, and DNA content was determined using CyQuant DNA dye. IC50 values were calculated. [1]
Client protein degradation assays (Her2, p-S6, p-ERK, Hsp70): A375 and AU565 cells were treated with compound for 24 h, then fixed with methanol. After fixation in 4% PBS-buffered formalin and permeabilization with 0.1% Triton X-100, cells were probed with primary antibodies (anti-Her2, anti-phospho-S6, anti-pERK, anti-Hsp70) followed by TRITC or FITC-conjugated secondary antibodies. Nuclei were stained with Hoechst. For each well, 250-500 individual nuclei were identified, and average staining intensity for each protein was calculated. IC50 values were determined. [1] |
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| Animal Protocol |
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| ADME/Pharmacokinetics |
Following oral administration of PF-04929113 mesylate (CAS#: 1173111-67-5) at 10 mg/kg in female mice: Tmax = 1 h, Cmax = 747 ng/mL, AUCinf = 3698 h·ng/mL, T1/2 = 2.5 h, VZ_F_obs = 9282 mL/kg, CL_F_obs = 2520 mL/h/kg. At 25 mg/kg oral: Tmax = 1 h, Cmax = 1481 ng/mL, AUCinf = 11004 h·ng/mL, T1/2 = 2.5 h, VZ_F_obs = 9954 mL/kg, CL_F_obs = 2272 mL/h/kg. At 50 mg/kg oral: Tmax = 2 h, Cmax = 2401 ng/mL, AUCinf = 15251 h·ng/mL, T1/2 = 3.3 h, VZ_F_obs = 3395 mL/kg, CL_F_obs = 1988 mL/h/kg. Following IV administration at 10 mg/kg: T1/2 = 0.8 h, VZ_F_obs = 846 mL/kg, CL_F_obs = 2054 mL/h/kg. Oral bioavailability was approximately 5%. Prodrug levels were below the lower limit of quantitation at all time points, indicating rapid conversion to the active parent SNX-2112. [1]
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| Toxicity/Toxicokinetics |
PF-04929113 mesylate (CAS#: 1173111-67-5) was well tolerated in mouse xenograft studies at oral doses up to 50 mg/kg. No treatment-related deaths were observed. Based on body weight measurements and clinical observations, the compound was well tolerated at all dose levels tested (5, 10, 25, 50 mg/kg). No specific toxicity data (e.g., LD50, hepatotoxicity) are reported. [1]
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| References | |||
| Additional Infomation |
SNX-5422 mesylate, an Hsp90 inhibitor, is a highly bioavailable synthetic prodrug that targets human heat shock protein 90 (Hsp90) and possesses potential antitumor activity. Although its mechanism of action is not fully elucidated, SNX-5422 is rapidly converted to SNX-2112, which accumulates in tumor tissues at a faster rate than in normal tissues. SNX-2112 inhibits Hsp90, which may lead to proteasomal degradation of oncogenic substrate proteins, including HER2/ERBB2, and inhibits tumor cell proliferation. Hsp90 is a molecular chaperone that plays a crucial role in the conformational maturation of oncogenic signaling proteins such as HER2/ERBB2, AKT, RAF1, BCR-ABL, and mutant p53, as well as many other molecules that play important roles in cell cycle regulation or immune responses.
PF-04929113 mesylate (CAS#: 1173111-67-5) (SNX-5422) is a prodrug designed to improve oral bioavailability of the poorly crystalline parent compound SNX-2112 (9). The prodrug is rapidly and completely converted to the active parent in vivo after oral and intravenous dosing. It is a highly selective Hsp90 inhibitor with no significant off-target interactions when screened against 75 enzymes and receptors at 1 μM (no inhibitory activity greater than 20%), and no significant inhibition against a panel of 9 cytochrome P450 isozymes. It is stable to human liver microsome metabolism (88% remaining after 1 h in S9 fractions). [1] |
| Molecular Formula |
C26H34F3N5O7S
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| Molecular Weight |
617.64
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| Exact Mass |
617.213
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| CAS # |
1173111-67-5
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| Related CAS # |
908115-27-5;1173111-67-5 (mesylate);
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| PubChem CID |
44195570
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| Appearance |
Typically exists as solid at room temperature
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| LogP |
5.612
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| Hydrogen Bond Donor Count |
4
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| Hydrogen Bond Acceptor Count |
13
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| Rotatable Bond Count |
7
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| Heavy Atom Count |
42
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| Complexity |
969
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| Defined Atom Stereocenter Count |
0
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| SMILES |
S(C([H])([H])[H])(=O)(=O)O[H].FC(C1C2C(C([H])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])C=2N(C2C([H])=C([H])C(C(N([H])[H])=O)=C(C=2[H])N([H])C2([H])C([H])([H])C([H])([H])C([H])(C([H])([H])C2([H])[H])OC(C([H])([H])N([H])[H])=O)N=1)=O)(F)F
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| InChi Key |
NVGFSTMGRRADRG-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C25H30F3N5O4.CH4O3S/c1-24(2)10-18-21(19(34)11-24)22(25(26,27)28)32-33(18)14-5-8-16(23(30)36)17(9-14)31-13-3-6-15(7-4-13)37-20(35)12-29;1-5(2,3)4/h5,8-9,13,15,31H,3-4,6-7,10-12,29H2,1-2H3,(H2,30,36);1H3,(H,2,3,4)
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| Chemical Name |
[4-[2-carbamoyl-5-[6,6-dimethyl-4-oxo-3-(trifluoromethyl)-5,7-dihydroindazol-1-yl]anilino]cyclohexyl] 2-aminoacetate;methanesulfonic acid
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| Synonyms |
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
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| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
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| Solubility (In Vivo) |
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| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.6191 mL | 8.0953 mL | 16.1907 mL | |
| 5 mM | 0.3238 mL | 1.6191 mL | 3.2381 mL | |
| 10 mM | 0.1619 mL | 0.8095 mL | 1.6191 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
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