Discovery and optimization of triazolopyridazines as potent and selective inhibitors of the c-Met kinase.
Tumorigenesis is a multistep process in which oncogenes play a key role in tumor formation, growth, and maintenance. MET was discovered as an oncogene that is activated by its ligand, hepatocyte growth factor. Deregulated signaling in the c-Met pathway has been observed in multiple tumor types. Herein we report the discovery of potent and selective triazolopyridazine small molecules that inhibit c-Met activity.
Albrecht
Brian K
BK
Amgen Inc., Cambridge, MA 02139, USA. brian.albrecht@amgen.com
Harmange
Jean-Christophe
JC
Bauer
David
D
Berry
Loren
L
Bode
Christiane
C
Boezio
Alessandro A
AA
Chen
April
A
Choquette
Deborah
D
Dussault
Isabelle
I
Fridrich
Cary
C
Hirai
Satoko
S
Hoffman
Doug
D
Larrow
Jay F
JF
Kaplan-Lefko
Paula
P
Lin
Jasmine
J
Lohman
Julia
J
Long
Alexander M
AM
Moriguchi
Jodi
J
O'Connor
Anne
A
Potashman
Michele H
MH
Reese
Monica
M
Rex
Karen
K
Siegmund
Aaron
A
Shah
Kavita
K
Shimanovich
Roman
R
Springer
Stephanie K
SK
Teffera
Yohannes
Y
Yang
Yajing
Y
Zhang
Yihong
Y
Bellon
Steven F
SF
D000818:Animals; D018360:Crystallography, X-Ray; D017228:Hepatocyte Growth Factor / Q000502:physiology; D066298:In Vitro Techniques; D051379:Mice; D008862:Microsomes, Liver / Q000378:metabolism; D008958:Models, Molecular; D015394:Molecular Structure; D010766:Phosphorylation; D019859:Proto-Oncogene Proteins c-met / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D011724:Pyridazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D013329:Structure-Activity Relationship; D014230:Triazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology
D011724:Pyridazines; D014230:Triazoles; D017228:Hepatocyte Growth Factor; D019859:Proto-Oncogene Proteins c-met