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.
Vertex Pharmaceuticals Incorporated, Cambridge, MA 02139, United States.
Jingrong
J
Cao
Huai
H
Gao
Guy
G
Bemis
Francesco
F
Salituro
Mark
M
Ledeboer
Edmund
E
Harrington
Susanne
S
Wilke
Paul
P
Taslimi
S
S
Pazhanisamy
Xiaoling
X
Xie
Marc
M
Jacobs
Jeremy
J
Green
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