N-(3-Cyano-4,5,6,7-tetrahydro-1-benzothien-2-yl)amides as potent, selective, inhibitors of JNK2 and JNK3 |
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| Authors: | Angell Richard M Atkinson Francis L Brown Murray J Chuang Tsu Tshen Christopher John A Cichy-Knight Maria Dunn Allison K Hightower Kendra E Malkakorpi Susanna Musgrave James R Neu Margarete Rowland Paul Shea Robyn L Smith Jeffery L Somers Donald O Thomas Sonia A Thompson Gladstone Wang Ruolan |
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| Affiliation: | GlaxoSmithKline R&D, Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, UK. |
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| Abstract: | 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. |
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