Background
PLX-4720, a 7-azaindole derivative discovered by a structure-guided discovery approach, is a potent inhibitor of B-RafV600E, the most frequent oncogenic protein kinase mutation, with the value of 50% inhibition concentration IC50 of 13 nM. PLX-4720 exhibits selective inhibition against B-RafV600E rather than wild type B-Raf (IC50 = 160 nM) as well as a wide range of other kinases, such as FRK, CSK, SRC, FAK, FGFR, and Aurora A (IC50 > 1000 nM for all). PLX-4720 potently inhibits ERK phosphorylation in tumor cell lines harboring B-RafV600E, induces cell cycle arrest and apoptosis in B-RafV600E-positive melanoma cells and causes tumor growth delays in B-RafV600E-dependent tumor xenograft models through oral administration.
Reference
[1].Tsai J, Lee JT, Wang W, Zhang J, Cho H, Mamo S, Bremer R, Gillette S, Kong J, Haass NK, Sproesser K, Li L, Smalley KS, Fong D, Zhu YL, Marimuthu A, Nguyen H, Lam B, Liu J, Cheung I, Rice J, Suzuki Y, Luu C, Settachatgul C, Shellooe R, Cantwell J, Kim SH, Schlessinger J, Zhang KY, West BL, Powell B, Habets G, Zhang C, Ibrahim PN, Hirth P, Artis DR, Herlyn M, Bollag G. Discovery of a selective inhibitor of oncogenic B-Raf kinase with potent antimelanoma activity. Proc Natl Acad Sci U S A. 2008 Feb 26;105(8):3041-3046
Protocol
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Cell experiment: [1]
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Cell lines
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WM793 cells
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Preparation method
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The solubility of this compound in DMSO is >10 mM. General tips for obtaining a higher concentration: Please warm the tube at 37 °C for 10 minutes and/or shake it in the ultrasonic bath for a while.Stock solution can be stored below -20°C for several months.
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Reaction Conditions
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0.5 μM, 96 hours
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Applications
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Viable cells were identified following 96 h incubation with PLX-4720. Cell viability was further evaluated after re-plating onto non-fibrillar collagen gels, in the continued presence of the drug. Viable cells were identified in ~63% of PLX-4720 treated cultures. These data indicate that melanoma cells harboring a BRAFV600E mutation can survive despite reductions in BRAF activation of the MEK-ERK signaling cascade.
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Animal experiment: [2]
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Animal models
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Athymic nude mice injected with melanoma A375 cells
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Dosage form
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Intraperitoneal injection, 25–50mg/kg daily
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Applications
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PLX-4720 decreased tumor growth as single therapy. When combined with the CRM1 inhibitor KPT-276 (75 mg/kg every day), the two inhibitors induced complete tumor regression per RECIST criteria. The difference between both single therapy and the combination therapy was statistically significant. The effect on apoptosis was believed to be the greatest contribution of the combination since it was significantly increased by the drug combination.
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Other notes
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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] Klein R M, Higgins P J. A switch in RND3-RHOA signaling is critical for melanoma cell invasion following mutant-BRAF inhibition. Mol Cancer, 2011, 10: 114.
[2] Fragomeni R A S, Chung H W, Landesman Y, et al. CRM1 and BRAF inhibition synergize and induce tumor regression in BRAF-mutant melanoma. Molecular cancer therapeutics, 2013, 12(7): 1171-1179.
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