MK-2461, a novel multitargeted kinase inhibitor, preferentially inhibits the activated c-Met receptor.
The receptor tyrosine kinase c-Met is an attractive target for therapeutic blockade in cancer. Here, we describe MK-2461, a novel ATP-competitive multitargeted inhibitor of activated c-Met. MK-2461 inhibited in vitro phosphorylation of a peptide substrate recognized by wild-type or oncogenic c-Met kinases (N1100Y, Y1230C, Y1230H, Y1235D, and M1250T) with IC(50) values of 0.4 to 2.5 nmol/L. In contrast, MK-2461 was several hundredfold less potent as an inhibitor of c-Met autophosphorylation at the kinase activation loop. In tumor cells, MK-2461 effectively suppressed constitutive or ligand-induced phosphorylation of the juxtamembrane domain and COOH-terminal docking site of c-Met, and its downstream signaling to the phosphoinositide 3-kinase-AKT and Ras-extracellular signal-regulated kinase pathways, without inhibiting autophosphorylation of the c-Met activation loop. BIAcore studies indicated 6-fold tighter binding to c-Met when it was phosphorylated, suggesting that MK-2461 binds preferentially to activated c-Met. MK-2461 displayed significant inhibitory activities against fibroblast growth factor receptor (FGFR), platelet-derived growth factor receptor, and other receptor tyrosine kinases. In cell culture, MK-2461 inhibited hepatocyte growth factor/c-Met-dependent mitogenesis, migration, cell scatter, and tubulogenesis. Seven of 10 MK-2461-sensitive tumor cell lines identified from a large panel harbored genomic amplification of MET or FGFR2. In a murine xenograft model of c-Met-dependent gastric cancer, a well-tolerated oral regimen of MK-2461 administered at 100 mg/kg twice daily effectively suppressed c-Met signaling and tumor growth. Similarly, MK-2461 inhibited the growth of tumors formed by s.c. injection of mouse NIH-3T3 cells expressing oncogenic c-Met mutants. Taken together, our findings support further preclinical development of MK-2461 for cancer therapy.
Department of In Vitro Sciences, Merck Research Laboratories, BMB-11, 33 Avenue Louis Pasteur, Boston, MA 02115, USA. bosheng_pan@merck.com
Bo-Sheng
BS
Pan
Grace K Y
GK
Chan
Melissa
M
Chenard
An
A
Chi
Lenora J
LJ
Davis
Sujal V
SV
Deshmukh
Jackson B
JB
Gibbs
Susana
S
Gil
Gaozhen
G
Hang
Harold
H
Hatch
James P
JP
Jewell
Ilona
I
Kariv
Jason D
JD
Katz
Kaiko
K
Kunii
Wei
W
Lu
Bart A
BA
Lutterbach
Cloud P
CP
Paweletz
Xianlu
X
Qu
John F
JF
Reilly
Alexander A
AA
Szewczak
Qinwen
Q
Zeng
Nancy E
NE
Kohl
Christopher J
CJ
Dinsmore
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D002478:Cells, Cultured; D004285:Dogs; D016503:Drug Delivery Systems / Q000379:methods; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D000882:Haplorhini; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D041681:NIH 3T3 Cells; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D019859:Proto-Oncogene Proteins c-met / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013379:Substrate Specificity / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D019859:Proto-Oncogene Proteins c-met