PLX-4720 is a selective BRAFV600E inhibitor with the IC50 values of 160 nM and 130 nM for B-Raf and BRK respectively. PLX-4720 shows remarkable selectivity for BRAF over a panel of 70 protein kinases due to its unusual binding mode, 40 and a similar selectivity is observed for its analogues. PLX-4720 has a BRAF IC50 of 13 nM, and in a panel of melanoma cell lines inhibits ERK activity only in those cell types that harbour the V600E mutation (pERK GI50 14–46 nM) whereas ERK remains unaffected in cells with WTBRAF.
|Cell lines||A375, UACC-903, and BRAF wt cell lines|
|Preparation method||Cell proliferation assays Cellular proliferation was evaluated by MTT assay (Sigma-Aldrich) following the manufacturer's instructions. Cells were plated in 96-well plates at 1,000 to 10,000 cells per well in 100 μL of media 24 hours after treatment and MTT signal was read at 72 hours after treatment. The IC50 and combination index (CI) by Chou–Talalay (16) were determined from the regression plot logarithm of the concentration versus effect using Calcusyn Software (Biosoft) v1.1. In addition, conservative isobolograms were used to show synergism and/or antagonism.|
|Animal models||Athymic nude mice Nu/Nu (Crl:NU-Foxn1nu) A375, A2058 (BRAF V600E-mutant), and Mel-Juso [BRAF wild-type (WT) and NRAS-mutant] xenograft tumor model|
|Formulation||dimethyl sulfoxide (DMSO)|
|Dosages||50 mg/kg everyday|
|Administration||intraperitoneal (i.p.) injections|
|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 ≥81 mg/mL|
|Source||Oncotarget (2016). Figure 5. PLX-4720|
|Cell Lines||A375R cells|
|Incubation Time||14 days|
|Results||Importantly, in vitro derived PLX-4720 resistant A375R cells (cultured in the presence of 1μM PLX-4720) were growth inhibited by SB-431542|
|Source||Oncotarget (2016). Figure 4. PLX-4720|
|Cell Lines||Colo829 and A375(M2) cells|
|Incubation Time||14 days|
|Results||Importantly cotreatment of PLX-4720 treated mutant BRAF cells with SB-431542 (10μM) abolished the increase in cell growth caused by low dose PLX-4720 (Figure 4d and 4e).|
Differential inhibitory effects of two Raf-targeting drugs, sorafenib and PLX4720, on the growth of multidrug-resistant cells.
Eum KH, et al. Mol Cell Biochem. 2012 Sep 2. PMID: 22941213.
BH3-only protein silencing contributes to acquired resistance to PLX4720 in human melanoma.
Shao Y, et al. Cell Death Differ. 2012 Aug 3. PMID: 22858545.
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