Discovery of pyrrolopyridine-pyridone based inhibitors of Met kinase: synthesis, X-ray crystallographic analysis, and biological activities.
Conformationally constrained 2-pyridone analogue 2 is a potent Met kinase inhibitor with an IC50 value of 1.8 nM. Further SAR of the 2-pyridone based inhibitors of Met kinase led to potent 4-pyridone and pyridine N-oxide inhibitors such as 3 and 4. The X-ray crystallographic data of the inhibitor 2 bound to the ATP binding site of Met kinase protein provided insight into the binding modes of these inhibitors, and the SAR of this series of analogues was rationalized. Many of these analogues showed potent antiproliferative activities against the Met dependent GTL-16 gastric carcinoma cell line. Compound 2 also inhibited Flt-3 and VEGFR-2 kinases with IC50 values of 4 and 27 nM, respectively. It possesses a favorable pharmacokinetic profile in mice and demonstrates significant in vivo antitumor activity in the GTL-16 human gastric carcinoma xenograft model.
Kim
Kyoung Soon
KS
Department of Oncology Chemistry, Bristol-Myers Squibb Pharmaceutical Research & Development, P.O. Box 4000, Princeton, New Jersey 08543-4000, USA. kyoung.kim@bms.com
Zhang
Liping
L
Schmidt
Robert
R
Cai
Zhen-Wei
ZW
Wei
Donna
D
Williams
David K
DK
Lombardo
Louis J
LJ
Trainor
George L
GL
Xie
Dianlin
D
Zhang
Yaquan
Y
An
Yongmi
Y
Sack
John S
JS
Tokarski
John S
JS
Darienzo
Celia
C
Kamath
Amrita
A
Marathe
Punit
P
Zhang
Yueping
Y
Lippy
Jonathan
J
Jeyaseelan
Robert
R
Wautlet
Barri
B
Henley
Benjamin
B
Gullo-Brown
Johnni
J
Manne
Veeraswamy
V
Hunt
John T
JT
Fargnoli
Joseph
J
Borzilleri
Robert M
RM
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D018360:Crystallography, X-Ray; D006801:Humans; D020128:Inhibitory Concentration 50; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008862:Microsomes, Liver / Q000378:metabolism; D010770:Phosphotransferases / Q000037:antagonists & inhibitors*; D047428:Protein Kinase Inhibitors; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors*; D019859:Proto-Oncogene Proteins c-met; D011728:Pyridones / Q000138:chemical synthesis / Q000494:pharmacology*; D017978:Receptors, Growth Factor / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors; D051941:fms-Like Tyrosine Kinase 3 / Q000037:antagonists & inhibitors
D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D011518:Proto-Oncogene Proteins; D011728:Pyridones; D017978:Receptors, Growth Factor; C017679:2-hydroxypyridine; D010770:Phosphotransferases; C491743:MET protein, human; D019859:Proto-Oncogene Proteins c-met; D040301:Vascular Endothelial Growth Factor Receptor-2; D051941:fms-Like Tyrosine Kinase 3