3,5-Disubstituted quinolines as novel c-Jun N-terminal kinase inhibitors.
The structure-based design and synthesis of a novel series of c-Jun N-terminal kinase (JNK) inhibitors with selectivity against p38 is reported. The unique structure of 3,5-disubstituted quinolines (2) was developed from the previously reported 4-(2,7-phenanthrolin-9-yl)phenol (1). The X-ray crystal structure of 16a in JNK3 reveals an unexpected binding mode for this new scaffold with protein.
Jiang
Rong
R
Department of Medicinal Chemistry, Scripps Florida, 5353 Parkside Drive, RF-2, Jupiter, FL 33458, USA. rjiang@scripps.edu
Duckett
Derek
D
Chen
Weiming
W
Habel
Jeff
J
Ling
Yuan Yuan
YY
LoGrasso
Philip
P
Kamenecka
Theodore M
TM
D018360:Crystallography, X-Ray; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors*; D015394:Molecular Structure; D010618:Phenanthrolines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D011485:Protein Binding / Q000187:drug effects; D011804:Quinolines / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors
D010618:Phenanthrolines; D011804:Quinolines; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases