N-(3-Cyano-4,5,6,7-tetrahydro-1-benzothien-2-yl)amides as potent, selective, inhibitors of JNK2 and JNK3.
The identification and exploration of a novel, potent and selective series of N-(3-cyano-4,5,6,7-tetrahydro-1-benzothien-2-yl)amide inhibitors of JNK2 and JNK3 kinases is described. Compounds 5a and 11a were identified as potent inhibitors of JNK3 (pIC50 6.7 and 6.6, respectively), with essentially equal potency against JNK2 (pIC50 6.5). Selectivity within the mitogen-activated protein kinase (MAPK) family, against JNK1, p38alpha and ERK2, was observed for the series. X-ray crystallography of 5e and 8a in JNK3 revealed a unique binding mode, with the 3-cyano substituent forming an H-bond acceptor interaction with the hinge region of the ATP-binding site.
Angell
Richard M
RM
GlaxoSmithKline R&D, Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, UK.
Atkinson
Francis L
FL
Brown
Murray J
MJ
Chuang
Tsu Tshen
TT
Christopher
John A
JA
Cichy-Knight
Maria
M
Dunn
Allison K
AK
Hightower
Kendra E
KE
Malkakorpi
Susanna
S
Musgrave
James R
JR
Neu
Margarete
M
Rowland
Paul
P
Shea
Robyn L
RL
Smith
Jeffery L
JL
Somers
Donald O
DO
Thomas
Sonia A
SA
Thompson
Gladstone
G
Wang
Ruolan
R
D000577:Amides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001555:Benzene Derivatives / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001665:Binding Sites; D018360:Crystallography, X-Ray; D006801:Humans; D048057:Mitogen-Activated Protein Kinase 10 / Q000037:antagonists & inhibitors* / Q000737:chemistry; D048056:Mitogen-Activated Protein Kinase 9 / Q000037:antagonists & inhibitors* / Q000737:chemistry; D013329:Structure-Activity Relationship
D000577:Amides; D001555:Benzene Derivatives; D048057:Mitogen-Activated Protein Kinase 10; D048056:Mitogen-Activated Protein Kinase 9