c-Jun N-terminal kinase (JNK) signaling: recent advances and challenges.
c-Jun N-terminal kinases (JNKs), first characterized as stress-activated members of the mitogen-activated protein kinase (MAPK) family, have become a focus of inhibitor screening strategies following studies that have shown their critical roles in the development of a number of diseases, such as diabetes, neurodegeneration and liver disease. We discuss recent advances in the discovery and development of ATP-competitive and ATP-noncompetitive JNK inhibitors. Because understanding the modes of actions of these inhibitors and improving their properties will rely on a better understanding of JNK structure, JNK catalytic mechanisms and substrates, recent advances in these areas of JNK biochemistry are also considered. In addition, the use of JNK gene knockout animals is continuing to reveal in vivo functions for these kinases, with tissue-specific roles now being dissected with tissue-specific knockouts. These latest advances highlight the many challenges now faced, particularly in the directed targeting of the JNK isoforms in specific tissues.
Bogoyevitch
Marie A
MA
Department of Biochemistry and Molecular Biology, Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, 30 Flemington Road, Parkville, Victoria 3010, Australia. marieb@unimelb.edu.au
Ngoei
Kevin R W
KR
Zhao
Teresa T
TT
Yeap
Yvonne Y C
YY
Ng
Dominic C H
DC
D000818:Animals; D002384:Catalysis; D003920:Diabetes Mellitus / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics; D055785:Gene Knockdown Techniques; D006801:Humans; D007527:Isoenzymes / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D048031:JNK Mitogen-Activated Protein Kinases / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D008107:Liver Diseases / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics; D020935:MAP Kinase Signaling System; D019636:Neurodegenerative Diseases / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000627:therapeutic use; D017434:Protein Structure, Tertiary / Q000235:genetics
D007527:Isoenzymes; D047428:Protein Kinase Inhibitors; D048031:JNK Mitogen-Activated Protein Kinases