PF-04880594RAF inhibitor CAS# 1111636-35-1 |
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Quality Control & MSDS
Number of papers citing our products
Chemical structure
3D structure
| Cas No. | 1111636-35-1 | SDF | Download SDF |
| PubChem ID | 53356806 | Appearance | Powder |
| Formula | C19H16F2N8 | M.Wt | 394.38 |
| Type of Compound | N/A | Storage | Desiccate at -20°C |
| Solubility | Soluble in DMSO | ||
| Chemical Name | 3-[[4-[1-(2,2-difluoroethyl)-3-(1H-pyrrolo[2,3-b]pyridin-5-yl)pyrazol-4-yl]pyrimidin-2-yl]amino]propanenitrile | ||
| SMILES | C1=CNC2=NC=C(C=C21)C3=NN(C=C3C4=NC(=NC=C4)NCCC#N)CC(F)F | ||
| Standard InChIKey | HFYMVDKBZONUOJ-UHFFFAOYSA-N | ||
| Standard InChI | InChI=1S/C19H16F2N8/c20-16(21)11-29-10-14(15-3-7-25-19(27-15)24-5-1-4-22)17(28-29)13-8-12-2-6-23-18(12)26-9-13/h2-3,6-10,16H,1,5,11H2,(H,23,26)(H,24,25,27) | ||
| 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-04880594 is an inhibitor of RAF with IC50 values of 0.19 nM/0.13 nM and 0.39 nM for BRAF/BRAFV599E and c-RAF, respectively. | |||||
| Targets | BRAFV599E | BRAF | c-RAF | |||
| IC50 | 0.13 nM | 0.19 nM | 0.39 nM | |||
PF-04880594 Dilution Calculator
PF-04880594 Molarity Calculator
| 1 mg | 5 mg | 10 mg | 20 mg | 25 mg | |
| 1 mM | 2.5356 mL | 12.6781 mL | 25.3563 mL | 50.7125 mL | 63.3906 mL |
| 5 mM | 0.5071 mL | 2.5356 mL | 5.0713 mL | 10.1425 mL | 12.6781 mL |
| 10 mM | 0.2536 mL | 1.2678 mL | 2.5356 mL | 5.0713 mL | 6.3391 mL |
| 50 mM | 0.0507 mL | 0.2536 mL | 0.5071 mL | 1.0143 mL | 1.2678 mL |
| 100 mM | 0.0254 mL | 0.1268 mL | 0.2536 mL | 0.5071 mL | 0.6339 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-04880594 is a selective inhibitor of B-Raf, B-RafV599E and c-Raf with IC50 value of 0.19 nM, 0.13 nM and 0.39 nM, respectively [1].
Raf is a serine/threonine protein kinase and plays an important role in the MAPK/ERK signaling pathway. It has been revealed that Raf involves in cancers and developmental syndromes and its inhibitors are regarded as a promising target for cancer treatment [2, 3].
PF-04880594 is a potent Raf inhibitor. When tested with GTL16 and GTL16 resistant cell clones, PF-04880594 treatment significantly decreased cell viability and ERK activity [2]. In 3D culture model of RHE cells (histologic similar to human epidermal lasers), PF-04880594 treatment (62.5 nmol/L, 2 d) significantly induced necrosis with ghost cells accounting for nearly 50% to 60% of the culture thickness via inducing p-ERK expression level [3].
Treated nude mice model with PF-04880594 (10-40 mg/kg, twice daily for 3 weeks) and then mice were sacrificed for further study. The results revealed that PF-04880594 treatment induced ERK phosphorylation and B-Raf-c-Raf dimerization in multiple epithelial tissues which phenomenon could be attenuated by PD-0325901 [3].
References:
[1]. Palmer C, Cui J, Deal J, Gu D, Guo C, Kephart S, et al. Discovery of potent, selective inhibitors of mutant B-Raf. (Abstract # MEDI-251). Abstracts of Papers, 242nd ACS National Meeting & Exposition 2011.
[2]. Lee, N. V. Lira, M. E. Pavlicek, A., et al. A novel SND1-BRAF fusion confers resistance to c-Met inhibitor PF-04217903 in GTL16 cells through [corrected] MAPK activation [J]. PLoS One, 2012, 7(6): e39653.
[3]. Vince R. Torti, Donald Wojciechowicz, Wenyue Hu, et al. Epithelial Tissue Hyperplasia Induced by the RAF Inhibitor PF-04880594 Is Attenuated by a Clinically Well-Tolerated Dose of the MEK Inhibitor PD-0325901 [J]. Mol Cancer Ther, 2012, 11(10):2274-2283.
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Epithelial tissue hyperplasia induced by the RAF inhibitor PF-04880594 is attenuated by a clinically well-tolerated dose of the MEK inhibitor PD-0325901.[Pubmed:22752429]
Mol Cancer Ther. 2012 Oct;11(10):2274-83.
Clinical trials of selective RAF inhibitors in patients with melanoma tumors harboring activated BRAFV600E have produced very promising results, and a RAF inhibitor has been approved for treatment of advanced melanoma. However, about a third of patients developed resectable skin tumors during the course of trials. This is likely related to observations that RAF inhibitors activate extracellular signal-regulated kinase (ERK) signaling, stimulate proliferation, and induce epithelial hyperplasia in preclinical models. Because these findings raise safety concerns about RAF inhibitor development, we further investigated the underlying mechanisms. We showed that the RAF inhibitor PF-04880594 induces ERK phosphorylation and RAF dimerization in those epithelial tissues that undergo hyperplasia. Hyperplasia and ERK hyperphosphorylation are prevented by treatment with the mitogen-activated protein/extracellular signal-regulated kinase (MEK) inhibitor PD-0325901 at exposures that extrapolate to clinically well-tolerated doses. To facilitate mechanistic and toxicologic studies, we developed a three-dimensional cell culture model of epithelial layering that recapitulated the RAF inhibitor-induced hyperplasia and reversal by MEK inhibitor in vitro. We also showed that PF-04880594 stimulates production of the inflammatory cytokine interleukin 8 in HL-60 cells, suggesting a possible mechanism for the skin flushing observed in dogs. The complete inhibition of hyperplasia by MEK inhibitor in epithelial tissues does not seem to reduce RAF inhibitor efficacy and, in fact, allows doubling of the PF-04880594 dose without toxicity usually associated with such doses. These findings indicated that combination treatment with MEK inhibitors might greatly increase the safety and therapeutic index of RAF inhibitors for the treatment of melanoma and other cancers.
