In vitro: BI-847325 shows growth-inhibitory effects on BRAF-mutant and vemurafenib-resistant melanoma cells with IC50 ranging from 0.3 nM to 2 μM, and prevents colony formation in six BRAF-mutant melanoma cell lines. BI-847325 also induces apoptosis by reducing Mcl-1 expression. In vivo: In mice bearing 1205Lu and 1205LuR xenografts, BI-847325 (75 mg/kg, p.o.) causes significant tumor suppression without significant alteration in the body weights.
|Cell lines||M229, M229R, A375, A375R, WM793, WM793R, 1205Lu, 1205LuR, M249, M249R, WM164, WM164R, WM39 and RPMI17951 cells|
|Preparation method||Cells are plated at a density of 2.5 × 10^3 cells per 100 μL and left to grow overnight before being treated with increasing concentrations of BI-847325 for 72 hours. The metabolic activity is determined using Alamar blue reagent as per the manufacturer's protocol.|
|Incubation time||72 h|
|Animal models||Mice bearing 1205Lu and 1205LuR xenografts|
|Formulation||2-hydroxyethyl cellulose, polysorbate 80 with pH adjusted to 2.8 with 1 M HCl|
|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||19 mg/mL warmed in DMSO|
Pharmacological Profile of BI 847325, an Orally Bioavailable, ATP-Competitive Inhibitor of MEK and Aurora Kinases.
Sini P, et al. Mol Cancer Ther. 2016 Oct;15(10):2388-2398. PMID: 27496137.
The Novel ATP-Competitive MEK/Aurora Kinase Inhibitor BI-847325 Overcomes Acquired BRAF Inhibitor Resistance through Suppression of Mcl-1 and MEK Expression.
Phadke MS, et al. Mol Cancer Ther. 2015 Jun;14(6):1354-64. PMID: 25873592.
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