Table 2.

Impact of MET mutations in proliferation and kinase assays

MutationBVU972PF-02341066AMG 458XL880
Cellular proliferation assay (IC50 ± SD), nmol/L
WT77 ± 2288 ± 24536 ± 6343 ± 12
Cellular proliferation assay (fold IC50 shift ± SD)
Y1230H>12911.6 ± 4.31.6 ± 0.50.7 ± 0.2
D1228A>12913.7 ± 2.21.9 ± 0.21.4 ± 0.4
V1155L14.6 ± 0.79.5 ± 1.02.8 ± 0.61.8 ± 0.3
F1200I14.1 ± 1.09.5 ± 1.58.0 ± 0.419.7 ± 0.7
L1195V31.5 ± 10.514.3 ± 2.6>186.9 ± 0.4
M1211L1.2 ± 0.31.0 ± 0.33.8 ± 1.32.4 ± 0.6
M1250T3.6 ± 0.72.9 ± 0.93.9 ± 1.11.7 ± 0.5
Biochemical assay (IC50), nmol/L
WT9438820
Biochemical assay (fold IC50 shift)
Y1230H3702.92.80.63
F1200I486.1334.1

NOTE: Top section: Antiproliferative activity of 4 structurally distinct MET inhibitors in BaF3 cells containing wild-type (WT) TPR-MET or the indicated mutant TPR-MET versions. Resistant clones from random mutagenesis screens were used. IC50 values for all mutants are expressed as fold shift in comparison to WT (n = 3). Comparable results were obtained with NVP-BVU972 and PF-02341066 in all other clones with Y1230 or D1228 mutations that occurred in the NVP-BVU972 resistance screen (data not shown). Bottom section: Inhibition of MET kinase activity in biochemical assays with WT and mutant recombinant proteins (n = 4 per protein).