| PLX4720 inhibits B-RafV600E with an IC50 of 13 nM, defines a class of kinase inhibitor with marked selectivity in both biochemical and cellular assays. PLX4720 inhibits kinases B-Raf, BRK, FRK, CSK, SRC, FAK, FGFR, KDR, HGK, CSF1R and AURORAA with IC50s of 0.16, 0.13, 1.3, 1.5, 1.7, 1.7, 1.9, 2.3, 2.8, 3.3 and 3.4 µM, respectively. PLX4720 inhibits B-RafV600E kinase activity in vitro at 10-fold lower concentrations than wild type B-Raf. PLX4720 clearly can cause regression of tumors in vivo. Indeed, increasing doses of PLX4720 up to 1,000 mg/kg resulted in increasing plasma levels (up to 600 µM) without any evidence of adverse reactions. [1] PLX4720 preferentially inhibits migration and invasion of B-RafV600E thyroid cancer cells and tumor aggressiveness. Normal thyroid cells are generated to be heterozygous for wild-type B-Raf/B-RafV600E, mimicking the condition found in most human thyroid cancers. PLX4720 is effective in reducing cell proliferation, migration, and invasion in heterozygous model.[2] B-RAFV600E melanoma cells selected for resistance to apoptosis induced by PLX4720 can proliferate, albeit with reduced growth rate, in the presence of the inhibitor.[3] PLX4720 inhibits the melanoma A375 cell line with an IC50 of 47 nM. In B-RafV600E-dependent tumor xenograft models, oral PLX4720 significantly reduces tumor growth and even causes tumor regression, without evidence of toxicity. [4] |
