Thursday 25 February 2010
PLX4032, RG7204, RO5185426, Zelboraf
Definition: The vemurafenib (PLX4032) is a selective BRAF-V600E mutant kinase inhibitor.
Vemurafenib is a selective small molecule inhibitor of BRAF It has recently been shown to be effective in the treatment of melanomas harboring the BRAF_V600E mutation.
Vemurafenib is also known as PLX4032, RG7204 or RO5185426, and has been marketed as Zelboraf.
Vemurafenib is a B-Raf enzyme inhibitor developed by Plexxikon (now part of the Daiichi Sankyo group) and Hoffmann–La Roche for the treatment of late-stage melanoma.
Vemurafenib received FDA approval for the treatment of late-stage melanoma on August 17, 2011.
Vemurafenib has been shown to cause programmed cell death in melanoma cell lines. Vemurafenib interrupts the B-Raf/MEK step on the B-Raf/MEK/ERK pathway − if the B-Raf has the common V600E mutation.
BRAF-V600E/K is a frequent mutationally active tumor-specific kinase in melanomas that is currently targeted for therapy by the specific inhibitor PLX4032.
It activates the ERK Pathway and enhances cell migration and proliferation of BRAF(WT) Melanoma Cells.
Studies with melanoma tumor cells that are BRAF(V600E/K) and BRAF(WT) showed that, paradoxically, while PLX4032 inhibited ERK1/2 in the highly sensitive BRAF(V600E/K).
It activated the pathway in the resistant BRAF(WT) cells, via RAF1 activation, regardless of the status of mutations in NRAS or PTEN.
The persistently active ERK1/2 triggered downstream effectors in BRAF(WT) melanoma cells and induced changes in the expression of a wide-spectrum of genes associated with cell cycle control.
PLX4032 increased the rate of proliferation of growth factor-dependent NRAS Q61L mutant primary melanoma cells, reduced cell adherence and increased mobility in of cells from advanced lesions.
The drug could confer an advantage to BRAF(WT) primary and metastatic tumor cells in vivo and provide markers for monitoring clinical responses. (#20149136#)
Similar to the broad-spectrum RAF inhibitor sorafenib, vemurafenib induces development of squamous cell carcinomas and keratoacanthomas as a side effect of therapy.
RAF inhibitors transactivate RAF dimers and ERK signalling in cells with wild-type BRAF. Poulikakos PI, Zhang C, Bollag G, Shokat KM, Rosen N. Nature. 2010 Feb 23. PMID: #20179705#
PLX4032, a Selective BRAF(V600E) Kinase Inhibitor, Activates the ERK Pathway and Enhances Cell Migration and Proliferation of BRAF(WT) Melanoma Cells. Halaban R, Zhang W, Bacchiocchi A, Cheng E, Parisi F, Ariyan S, Krauthammer M, McCusker JP, Kluger Y, Sznol M. Pigment Cell Melanoma Res. 2010 Feb 10. PMID: #20149136#
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BRAF silencing by short hairpin RNA or chemical blockade by PLX4032 leads to different responses in melanoma and thyroid carcinoma cells. Sala E, Mologni L, Truffa S, Gaetano C, Bollag GE, Gambacorti-Passerini C. Mol Cancer Res. 2008 May;6(5):751-9. PMID: #18458053#