Structure-based design and parallel synthesis of N-benzyl isatin oximes as JNK3 MAP kinase inhibitors.
A series of N-benzylated isatin oximes were developed as inhibitors of the mitogen-activated kinase, JNK3. X-ray crystallographic structures aided in the design and synthesis of novel, selective compounds, that inhibit JNK3, but not p38 MAP kinase and provided key insights into understanding the behavior of gatekeeper residue methionine-146 in determining target selectivity for this series.
Cao
Jingrong
J
Vertex Pharmaceuticals Incorporated, Cambridge, MA 02139, United States.
Gao
Huai
H
Bemis
Guy
G
Salituro
Francesco
F
Ledeboer
Mark
M
Harrington
Edmund
E
Wilke
Susanne
S
Taslimi
Paul
P
Pazhanisamy
S
S
Xie
Xiaoling
X
Jacobs
Marc
M
Green
Jeremy
J
D020134:Catalytic Domain; D018360:Crystallography, X-Ray; D015195:Drug Design; D007510:Isatin / Q000138:chemical synthesis / Q000737:chemistry*; D048057:Mitogen-Activated Protein Kinase 10 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D010091:Oximes / Q000138:chemical synthesis / Q000737:chemistry*; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry; D013329:Structure-Activity Relationship
D010091:Oximes; D047428:Protein Kinase Inhibitors; D007510:Isatin; D048057:Mitogen-Activated Protein Kinase 10