Structure-based design of novel class II c-Met inhibitors: 1. Identification of pyrazolone-based derivatives.
Deregulation of c-Met receptor tyrosine kinase activity leads to tumorigenesis and metastasis in animal models. More importantly, the identification of activating mutations in c-Met, as well as MET gene amplification in human cancers, points to c-Met as an important target for cancer therapy. We have previously described two classes of c-Met kinase inhibitors (class I and class II) that differ in their binding modes and selectivity profiles. The class II inhibitors tend to have activities on multiple kinases. Knowledge of the binding mode of these molecules in the c-Met protein led to the design and evaluation of several new class II c-Met inhibitors that utilize various 5-membered cyclic carboxamides to conformationally restrain key pharmacophoric groups within the molecule. These investigations resulted in the identification of a potent and novel class of pyrazolone c-Met inhibitors with good in vivo activity.
Department of Medicinal Chemistry, Amgen Inc., One Amgen Center Drive, Thousand Oaks, California 91320, USA. markn@amgen.com
Mark H
MH
Norman
Longbin
L
Liu
Matthew
M
Lee
Ning
N
Xi
Ingrid
I
Fellows
Noel D
ND
D'Angelo
Celia
C
Dominguez
Karen
K
Rex
Steven F
SF
Bellon
Tae-Seong
TS
Kim
Isabelle
I
Dussault
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D045744:Cell Line, Tumor; D018360:Crystallography, X-Ray; D015195:Drug Design; D006801:Humans; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008958:Models, Molecular; D010766:Phosphorylation; D011487:Protein Conformation; D019859:Proto-Oncogene Proteins c-met / Q000037:antagonists & inhibitors* / Q000378:metabolism; D047069:Pyrazolones / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017526:Receptor, IGF Type 1 / Q000037:antagonists & inhibitors; D013329:Structure-Activity Relationship; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors
D000970:Antineoplastic Agents; D047069:Pyrazolones; D019859:Proto-Oncogene Proteins c-met; D017526:Receptor, IGF Type 1; D040301:Vascular Endothelial Growth Factor Receptor-2