Targeting the JNK MAPK cascade for inhibition: basic science and therapeutic potential.
The c-Jun N-terminal protein kinases (JNKs) form one subfamily of the mitogen-activated protein kinase (MAPK) group of serine/threonine protein kinases. The JNKs were first identified by their activation in response to a variety of extracellular stresses and their ability to phosphorylate the N-terminal transactivation domain of the transcription factor c-Jun. One approach to study the function of the JNKs has included in vivo gene knockouts of each of the three JNK genes. Whilst loss of either JNK1 or JNK2 alone appears to have no serious consequences, their combined knockout is embryonic lethal. In contrast, the loss of JNK3 is not embryonic lethal, but rather protects the adult brain from glutamate-induced excitotoxicity. This latter example has generated considerable enthusiasm with JNK3, considered an appropriate target for the treatment of diseases in which neuronal death should be prevented (e.g. stroke, Alzheimer's and Parkinson's diseases). More recently, these gene knockout animals have been used to demonstrate that JNK could provide a suitable target for the protection against obesity and diabetes and that JNKs may act as tumour suppressors. Considerable effort is being directed to the development of chemical inhibitors of the activators of JNKs (e.g. CEP-1347, an inhibitor of the MLK family of JNK pathway activators) or of the JNKs themselves (e.g. SP600125, a direct inhibitor of JNK activity). These most commonly used inhibitors have demonstrated efficacy for use in vivo, with the successful intervention to decrease brain damage in animal models (CEP-1347) or to ameliorate some of the symptoms of arthritis in other animal models (SP600125). Alternative peptide-based inhibitors of JNKs are now also in development. The possible identification of allosteric modifiers rather than direct ATP competitors could lead to inhibitors of unprecedented specificity and efficacy.
Bogoyevitch
Marie A
MA
Cell Signalling Laboratory, Biochemistry and Molecular Biology, School of Biomedical and Chemical Sciences, University of Western Australia, Crawley, WA 6009, Australia. marieb@cyllene.uwa.edu.au
Boehm
Ingrid
I
Oakley
Aaron
A
Ketterman
Albert J
AJ
Barr
Renae K
RK
D000595:Amino Acid Sequence; D000818:Animals; D000873:Anthracenes / Q000737:chemistry / Q000494:pharmacology; D002227:Carbazoles / Q000737:chemistry / Q000494:pharmacology; D002986:Clinical Trials as Topic; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D007211:Indoles / Q000737:chemistry / Q000494:pharmacology; D048031:JNK Mitogen-Activated Protein Kinases; D020935:MAP Kinase Signaling System / Q000187:drug effects* / Q000502:physiology*; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010455:Peptides / Q000737:chemistry / Q000494:pharmacology
D000873:Anthracenes; D002227:Carbazoles; D004791:Enzyme Inhibitors; D007211:Indoles; D010455:Peptides; C106592:3,9-bis((ethylthio)methyl)-K-252a; C432165:pyrazolanthrone; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases