PF-5274857Smo antagonist,potent and selective CAS# 1373615-35-0 |
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Quality Control & MSDS
3D structure
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| Cas No. | 1373615-35-0 | SDF | Download SDF |
| PubChem ID | 56956240 | Appearance | Powder |
| Formula | C20H25ClN4O3S | M.Wt | 436.96 |
| Type of Compound | N/A | Storage | Desiccate at -20°C |
| Solubility | DMSO : 125 mg/mL (286.07 mM; Need ultrasonic) | ||
| Chemical Name | 1-[4-[5-chloro-4-(3,5-dimethylpyridin-2-yl)pyridin-2-yl]piperazin-1-yl]-3-methylsulfonylpropan-1-one | ||
| SMILES | CC1=CC(=C(N=C1)C2=CC(=NC=C2Cl)N3CCN(CC3)C(=O)CCS(=O)(=O)C)C | ||
| Standard InChIKey | BBVNTTZIOTWDSV-UHFFFAOYSA-N | ||
| Standard InChI | InChI=1S/C20H25ClN4O3S/c1-14-10-15(2)20(23-12-14)16-11-18(22-13-17(16)21)24-5-7-25(8-6-24)19(26)4-9-29(3,27)28/h10-13H,4-9H2,1-3H3 | ||
| General tips | For obtaining a higher solubility , please warm the tube at 37 ℃ and shake it in the ultrasonic bath for a while.Stock solution can be stored below -20℃ for several months. We recommend that you prepare and use the solution on the same day. However, if the test schedule requires, the stock solutions can be prepared in advance, and the stock solution must be sealed and stored below -20℃. In general, the stock solution can be kept for several months. Before use, we recommend that you leave the vial at room temperature for at least an hour before opening it. |
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| About Packaging | 1. The packaging of the product may be reversed during transportation, cause the high purity compounds to adhere to the neck or cap of the vial.Take the vail out of its packaging and shake gently until the compounds fall to the bottom of the vial. 2. For liquid products, please centrifuge at 500xg to gather the liquid to the bottom of the vial. 3. Try to avoid loss or contamination during the experiment. |
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| Shipping Condition | Packaging according to customer requirements(5mg, 10mg, 20mg and more). Ship via FedEx, DHL, UPS, EMS or other couriers with RT, or blue ice upon request. | ||
| Description | PF-5274857 is a potent and selective antagonist of Smoothened (Smo) with IC50 and Ki values of 5.8 nM and 4.6 nM, respectively. | |||||
| Targets | Smoothened | |||||
| IC50 | 5.8 nM (Ki=4.6 nM) | |||||
PF-5274857 Dilution Calculator
PF-5274857 Molarity Calculator
| 1 mg | 5 mg | 10 mg | 20 mg | 25 mg | |
| 1 mM | 2.2885 mL | 11.4427 mL | 22.8854 mL | 45.7708 mL | 57.2135 mL |
| 5 mM | 0.4577 mL | 2.2885 mL | 4.5771 mL | 9.1542 mL | 11.4427 mL |
| 10 mM | 0.2289 mL | 1.1443 mL | 2.2885 mL | 4.5771 mL | 5.7213 mL |
| 50 mM | 0.0458 mL | 0.2289 mL | 0.4577 mL | 0.9154 mL | 1.1443 mL |
| 100 mM | 0.0229 mL | 0.1144 mL | 0.2289 mL | 0.4577 mL | 0.5721 mL |
| * Note: If you are in the process of experiment, it's necessary to make the dilution ratios of the samples. The dilution data above is only for reference. Normally, it's can get a better solubility within lower of Concentrations. | |||||
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PF-5274857 is an inhibitor of hedgehog (Hh) signaling pathway and is identified as a potent and selective antagonist of Smoothened (Smo) with an IC50 of 5.8 nM.
Smoothened, a G protein-coupled receptor, is a component of the hedgehog signaling pathway and is conserved from flies to humans. This protein is the molecular target of the teratogen cyclopamine. SMO can act as an oncogene and the activation of SMO mutations leads to unregulated activation of the hedgehog pathway and cancer.
In MEF cells, treatment of PF-5274857 completely blocked Shh-induced Hh pathway activity, which was measured by the transcriptional activity of Smo downstream gene Gli1.
In vivo, PF-5274857 showed anti-tumor activity in a mouse medulloblastoma model with IC50 of 8.9 nM. PF-5274857 also shows significant dose-dependent tumor growth inhibition (TGI) and induces tumor regression. In skin tissue, downregulation of Gli1 and Gli2 is also observed with a similar time course by PF-52748571.
Reference:
1. Rohner A, Spilker ME, Lam JL, et al. Effective targeting of Hedgehog signaling in a medulloblastoma model with PF-5274857, a potent and selective Smoothened antagonist that penetrates the blood-brain barrier. Molecular cancer therapeutics.2012;11(1):57-65.
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Effective targeting of Hedgehog signaling in a medulloblastoma model with PF-5274857, a potent and selective Smoothened antagonist that penetrates the blood-brain barrier.[Pubmed:22084163]
Mol Cancer Ther. 2012 Jan;11(1):57-65.
Inhibition of the Smoothened (Smo) represents a promising therapeutic strategy for treating malignant tumors that are dependent on the Hedgehog (Hh) signaling pathway. PF-5274857 is a novel Smo antagonist that specifically binds to Smo with a K(i) of 4.6 +/- 1.1 nmol/L and completely blocks the transcriptional activity of the downstream gene Gli1 with an IC(50) of 2.7 +/- 1.4 nmol/L in cells. This Smo antagonist showed robust antitumor activity in a mouse model of medulloblastoma with an in vivo IC(50) of 8.9 +/- 2.6 nmol/L. The downregulation of Gli1 is closely linked to the tumor growth inhibition in patched(+/-) medulloblastoma mice. Mathematical analysis of the relationship between the drug's pharmacokinetics and Gli1 pharmacodynamics in patched(+/-) medulloblastoma tumor models yielded similar tumor and skin Gli1 IC(50) values, suggesting that skin can be used as a surrogate tissue for the measurement of tumor Gli1 levels. In addition, PF-5274857 was found to effectively penetrate the blood-brain barrier and inhibit Smo activity in the brain of primary medulloblastoma mice, resulting in improved animal survival rates. The brain permeability of PF-5274857 was also confirmed and quantified in nontumor-bearing preclinical species with an intact blood-brain barrier. PF-5274857 was orally available and metabolically stable in vivo. These findings suggest that PF-5274857 is a potentially attractive clinical candidate for the treatment of tumor types including brain tumors and brain metastasis driven by an activated Hh pathway.
