PLX8394 potently inhibits phosphorylation of ERK1/2 in PRT #3 and PRT #4 cells at >25 nM and in addition to parental cells at 10 nM. PLX8394 effectively reduces cyclin D3 and cyclin D1, phosphorylation of retinoblastoma protein, and expression of cyclin A2 in parental cells and PRT #3 and PRT #4 cells. PLX8394 inhibits ERK1/2 phosphorylation and the growth of vemurafenib-resistant cells harboring either a BRAF V600K/L505H double mutation or an transposon-induced, N-terminal truncated form of BRAF.
In vivo, PLX8394 (150 mg/kg/d) substantially suppresses tumor growth, MAPK pathway signaling and tumor cell proliferation in these H1755 xenograft tumors without overt toxicity in mice.
|Body Surface Area (m2)||0.007||0.025||0.15||0.05||0.02||0.5|
|Animal A (mg/kg) = Animal B (mg/kg) multiplied by||Animal B Km|
|Animal A Km|
For example, to modify the dose of resveratrol used for a mouse (22.4 mg/kg) to a dose based on the BSA for a rat, multiply 22.4 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for resveratrol of 11.2 mg/kg.
|Solubility||DMSO: ≥ 30 mg/mL|
Preclinical efficacy of a RAF inhibitor that evades paradoxical MAPK pathway activation in protein kinase BRAF-mutant lung cancer.
Okimoto RA, et al. Proc Natl Acad Sci U S A. 2016 Nov 22;113(47):13456-13461. PMID: 27834212.
RAF inhibitors that evade paradoxical MAPK pathway activation.
Zhang C, et al. Nature. 2015 Oct 22;526(7574):583-6. PMID: 26466569.
Inhibition of mutant BRAF splice variant signaling by next-generation, selective RAF inhibitors.
Basile KJ, et al. Pigment Cell Melanoma Res. 2014 May;27(3):479-84. PMID: 24422853.
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L-779450 is a potent, ATP-competitive Raf kinase inhibitor (IC50 =10 nM) that displays > 7, > 30 and > 70-fold selectivity over p38α, GSK3β and Lck respectively.
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