Identification of amidoheteroaryls as potent inhibitors of mutant (V600E) B-Raf kinase with in vivo activity.
A series of amidoheteroaryl compounds were designed and synthesized as inhibitors of B-Raf kinase. Several compounds from the series show excellent potency in biochemical, phenotypic and mode of action cellular assays. Potent examples from the series have also demonstrated good plasma exposure following an oral dose in rodents and activity against the Ras-Raf pathway in tumor bearing mice.
Lyne
Paul D
PD
Cancer Research, AstraZeneca R&D Boston, 35 Gatehouse Drive, Waltham, MA 02451, USA. paul.lyne@astrazeneca.com
Aquila
Brian
B
Cook
Donald J
DJ
Dakin
Les A
LA
Ezhuthachan
Jay
J
Ioannidis
Stephanos
S
Pontz
Timothy
T
Su
Mei
M
Ye
Qing
Q
Zheng
Xiaolan
X
Block
Michael H
MH
Cowen
Scott
S
Deegan
Tracy L
TL
Lee
John W
JW
Scott
David A
DA
Custeau
Dominique
D
Drew
Lisa
L
Poondru
Srinivasu
S
Shen
Minhui
M
Wu
Allan
A
D000284:Administration, Oral; D000818:Animals; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D006801:Humans; D020128:Inhibitory Concentration 50; D051379:Mice; D008956:Models, Chemical; D009154:Mutation; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors*; D051381:Rats; D013329:Structure-Activity Relationship; D048490:raf Kinases / Q000378:metabolism; D018631:ras Proteins / Q000378:metabolism
D004791:Enzyme Inhibitors; D048493:Proto-Oncogene Proteins B-raf; D048490:raf Kinases; D018631:ras Proteins