JNK pathway

Inhibitors of MLK (MKKK) [27], MKK4, 7 and JNK [6,28,29] have been disclosed to date. CEP-1347, a semi-synthetic analog of the natural product K252a, inhibits MLKs in the JNK pathway with K = 17 nM [30-32]. This compound has shown neuroprotective effects in cellular and animal models [33]. CEP-1347, an orally available compound that was well tolerated in the clinic, was advanced to Phase II/III trials for assessing efficacy in Parkinson s disease. However, the clinical trial was stopped due to a lack of significant efficacy [34], 

Compounds 4 and 5 and their analogs have been disclosed as MKK4 and 7 inhibitors [35,36]. The compounds in these patent applications are claimed to inhibit the two enzymes with IC50 1 gM no information on kinase specificity or other biological properties was disclosed. There are numerous other compounds that are disclosed in the patent literature to inhibit many kinases including MKK4 and 7 such compounds are not listed here. 

A number of distinct chemotypes have been reported as JNK inhibitors. In addition, a significant number of p38 inhibitors have also been found to have JNK inhibitory activity. This review will primarily focus on specific JNK inhibitors which have little or no p38 activity. 

SP-600125 was one of the first JNK inhibitors to be reported with potent JNK 1, 2 and 3 inhibitory activity (IC50 = 40,40 and 90 nM, respectively) [37], This tool compound has been studied extensively in a variety of cellular and animal models of inflammation and neuroprotection, among others. The profile of SP-600125 has been discussed in a number of reviews [6,28,29] and will not be discussed here. 

CC-401, whose structure has not yet been reported, is a potent and selective inhibitor of JNK1,2 and 3 (pan-JNK inhibitor), that has been advanced to Phase II clinical trials [38]. Celgene has disclosed analogs of compounds 6 and 7 as JNK inhibitors [39,40]. However, a recent patent application claims the crystal forms and other properties of 8, suggesting that it is likely to be a clinical candidate [41]. 

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SAPK/JNK pathway. Within the SAPK (stress-activated protein kinase) class, the Jun NT-terminal kinases (JNKs) form a subfamily (SAPK/JNK 1-3). 

Chatterjee, S., Kundu, S., Bhattacharyya, A., Hartinger, C. Dyson, P. The ruthenium(II)-arene compound RAPTA-C induces apoptosis in EAC cells through mitochondrial and p53-JNK pathways. /. Biol. Inorg. Chem. 13, 1149-1155 (2008). 

Wang, W., et al.. Activation of the hematopoietic progenitor kinase-1 (HPKl)-dependent, stress-activated c-Jun N-terminal kinase (JNK) pathway by transforming growth factor beta (TGF-beta)-activated kinase (TAKl), a kinase mediator of TGF beta signal transduction. J Biol Chem, 1997,... 

Kobuchi, H., Roy, S., Sen, C.K., Nguyen, H.G., and Packer, L., Quercetin inhibits inducible ICAM-1 expression in human endothelial cells through the JNK pathway. Am. J. Physiol, 277, C403, 1999. 

Kiefer F, Tibbies LA, Anafi M, Janssen A, et al. 1996. HPK1, a hematopoietic protein kinase activating the SAPK/JNK pathway. EMBO J. 16 7013-7025. 

Harris CA, Johnson EM Jr (2001), BH3-only Bcl-2 family members are coordinately regulated by the JNK pathway and require Bax to induce apoptosis in neurons, J. Biol. Chem. 276 37754-37760. 

Luo Y, Kokkonen GC, Wang X, Neve KA, Roth GS (1998) D2 dopamine receptors stimulate mitogenesis through pertussis toxin-sensitive G proteins and Ras-involved ERK and SAP/JNK pathways in rat C6-D2L glioma cells. J Neurochem 71 980-990. 

JIP-1 is a JNK pathway scaffold protein essential for JNK activation in some systems. Like many substrates, JIP-1 binds to JNK in the region generally called the common docking site in MAPKs (28). With the identification of the key residues of JNK required for interaction with the kinase interaction motif of JIP-1, small peptide inhibitors (TI-JIP RPKRPTTLNLF) derived from JIP have been described (29). As expected, TI-JIP was found to be competitive with respect to the phosphoaccep-tor substrate c-Jun and to exhibit noncompetitive inhibition with respect to ATP. It is not yet clear whether peptidomimetics or small molecule inhibitors that might have clinical applicability will be developed using information from JNK-JIP-1 interactions. 

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