BI-847325

BI-847325 is an ATP competitive dual inhibitor of MEK and aurora kinases (AK) with IC50 values of 4 and 15 nM for human MEK2 and AK-C, respectively.

Research Areas >> Cancer

MEK2:4 nM (IC50)

Aurora C:15 nM (IC50)

BI 847325 inhibits the activity of X. laevis AK-B with an IC50 of 3 nM; the IC50 values for human AK-A and AK-C are 25 and 15 nM, respectively. BI 847325 also inhibits human MEK1 and MEK2 with respective IC50 values of 25 and 4 nM. BI 847325 at 1,000 nM inhibits 6 enzymes by more than 50% (LCK, MAP3K8, FGFR1, AMPK, CAMK1D and TBK1) and the IC50 values are below 100 nM only for LCK (5 nM) and MAP3K8 (93 nM). Proliferation is inhibited in A375 and Calu-6 cell lines with GI50 values of 7.5 nM and 60 nM, respectively[1].

Daily oral administration of BI 847325 at 10 mg/kg shows efficacy in both BRAF- and KRAS-mutant xenograft models. BI 847325 administered once weekly at 70 mg/kg inhibits both MEK and AK in KRAS-mutant tumors[1].

Assays are run in the presence of 100 μM ATP using 10 μM of substrate. 30 μL PROTEIN-MIX in 25% DMSO and incubated for 15 min at room temperature. 10 μL PEPTIDE-MIX is added, the mixture is incubated for 60 min at RT and stopped by adding 180 μL 6.4% TCA (final concentration: 5%). Incorporated phosphate is measured in a scintillation counter and IC50 values are calculated using a sigmoidal curve analysis program with variable hill slope[1].

Cells are plated in 96-well format and BI 847325 is added 24 hours after cell seeding. At the same time, a “time zero” untreated cell plate is fixed. Compound is serially diluted and assayed over 8 concentrations in triplicates. After 72 h incubation, cells are fixed and stained with fluorescent nuclear dye. Concentration–response curves are analyzed using a four-parameter log-logistic function without upper or lower limitation. GI50 are calculated[1].

Mice: Tumor grafted female BomTac:NMRI-Foxn1nu mice are used in the study. BI 847325 is dissolved in 0.5% Natrosol 250 HX with 3% Tween 80 and sonicated until a homogenous suspension is obtained, then 1 M HCl is added and the suspension is vortexed and sonicated again. MEK inhibitors GSK 1120212 and AZD 6244 are suspended in 1% or 0.5% Natrosol, respectively. An administration volume of 10 mL/kg body weight is used and compounds are administered orally with a gavage needle at the indicated dose and schedule. Tumor volumes are measured and mice are inspected daily for clinical signs and body weight is determined daily[1].

[1]. Sini P, et al. Pharmacological Profile of BI 847325, an Orally Bioavailable, ATP-Competitive Inhibitor of MEK and Aurora Kinases. Mol Cancer Ther. 2016 Oct;15(10):2388-2398.

U0126-EtOH | PD98059 | Trametinib (GSK1120212) | PD0325901 | Selumetinib (AZD6244) | Alisertib (MLN8237) | Cobimetinib | MEK162(ARRY-162,ARRY-438162) | Tozasertib | AT9283 | Barasertib (AZD1152-HQPA) | danusertib | PD184352 (CI-1040) | Hesperadin | Reversine