A potent inhibitor of Raf-1
GW5074 is a synthetic inhibitor of c-Raf with IC50 value of 9nM [1].
GW5074 is found to be a potent inhibitor of c-Raf and has no effect on cdk1, cdk2, c-src, p38 MAP kinase, VEGFR2 and c-fms. GW5074 also shows no direct effect on JNK proteins and p38 MAP kinase. In neurons, GW5074 reduces the phosphorylation level of c-Raf at Ser259, results in an induction of c-Raf activity. It is further proved that GW5074 shows neuroprotective efficacy when its dose is below 1μM. In addition, GW5074 suppresses cell apoptosis through delaying the down-regulation of Akt phosphorylation and preventing the activation of GSK3β. In the in vivo model of Huntington’s disease, GW5074 protects neurons via resisting 3-NP-induced striatal neurodegeneration [1].
参考文献:
[1] Burgess S, Echeverria V. Raf inhibitors as therapeutic agents against neurodegenerative diseases. CNS & Neurological Disorders-Drug Targets (Formerly Current Drug Targets-CNS & Neurological Disorders), 2010, 9(1): 120-127.
| Cell experiment [1]: | |
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Cell lines |
Cerebellar granule neurons |
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Preparation method |
The solubility of this compound in DMSO is >26.1mg/mL. General tips for obtaining a higher concentration: Please warm the tube at 37℃ for 10 minutes and/or shake it in the ultrasonic bath for a while. Stock solution can be stored below -20℃ for several months. |
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Reacting condition |
1 μM, 40 min |
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Applications |
Treatment of neurons with GW5074 caused c-Raf activation and stimulated the Raf-MEK-ERK pathway. Treatment of neurons with GW5074 led increased the activity of B-Raf. GW5074 inhibited cell death caused by neurotoxins in granule cells and other neuronal types. |
| Animal experiment [1,2]: | |
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Animal models |
C57BL/6 male mice with Huntington’s disease (HD), Mice repeatedly exposed to smoke from four cigarettes each day for four weeks |
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Dosage form |
Intraperitoneal injection, 2 mg/kg, every day for three weeks |
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Application |
GW5074 (5 mg/kg) completely prevented extensive bilateral striatal lesions induced by 3-NP in C57BL/6 male mice. GW5074 (0.5 mg/kg or 2 mg/kg) suppressed side stream smoke-induced airway hyperresponsiveness in mice. |
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Other notes |
Please test the solubility of all compounds indoor, and the actual solubility may slightly differ with the theoretical value. This is caused by an experimental system error and it is normal. |
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参考文献: [1]. Chin P C, Liu L, Morrison B E, et al. The c‐Raf inhibitor GW5074 provides neuroprotection in vitro and in an animal model of neurodegeneration through a MEK‐ERK and Akt‐independent mechanism[J]. Journal of neurochemistry, 2004, 90(3): 595-608. [2]. Lei Y, Cao Y X, Xu C B, et al. The Raf-1 inhibitor GW5074 and dexamethasone suppress sidestream smoke-induced airway hyperresponsiveness in mice[J]. Respiratory research, 2008, 9(1): 71. | |
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