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MAP Kinase 2015; volume 4:5700 JNK inhibitors: unicellular organisms such as yeast and multi- cellular organisms such as plants, fungi, and Correspondence: Jonas Cicenas, MAP Kinase is there a future? vertebrates. There are three different alterna- Resource, Melchiorstrasse 9, CH-3027, Bern, tively spliced genes MAPK8 (JNK1), MAPK9 Switzerland. Jonas Cicenas (JNK2), and MAPK10 (JNK3) that produce ten E-mail: [email protected] MAP Kinase Resource and Institute of different isoforms. JNK1 and JNK2 are ubiqui- Key words: JNK inhibitors; editorial. Animal Pathology, Bern, Switzerland; tously expressed but JNK3 is expressed prima- rily in the nervous system.12-15 JNKs are acti- Vetsuisse Faculty, University of Bern and Conflict of interest: the author reports no conflict Proteomics Centre, Bern, Switzerland; vated by phosphorylation in the activation loop of interest. Institute of Biochemistry, Vilnius at residues Thr183/Tyr185 (JNK1, JNK2) or University, Lithuania pThr-221 and pTyr-223 (JNK3) by the MAP2Ks: Received for publication: 20 December 2015. MAP2K4 (MKK4), MAP2K5 (MKK5) and Accepted for publication: 21 December 2015. MAP2K7 (MKK7), and are dephosphorylated and thus deactivated by MAP kinase phos- This work is licensed under a Creative Commons phatases including DUSP1 (MKP1) and Attribution NonCommercial 3.0 License (CC BY- Abstract DUSP10 (MKP5). Signaling through the JNK- NC 3.0). pathway is organized through binding to scaf- ©Copyright J. Cicenas, 2015 JNK is a subfamily of MAP kinases that hat 16 fold proteins such as MAPK8IP1 (JIP1), Licensee PAGEPress, Italy regulates a range of biological processes impli- MAPK8IP2 (JIP2), MAPK8IP3 (JIP3), SPAG9 MAP Kinase 2015; 4:5700 cated in response to stress, such as cytokines, (JIP4)17 or WDR62,18 which assemble signal- doi:10.4081/mk.2015.5700 ultraviolet irradiation, heat shock, and osmotic ing complexes containing MAP3K, MAP2K and shock as well as growth factors like PDGF, EGF, MAPKs in addition to JNK-phosphorylated FGF, etc. They were originally identified as transcription factors such as JUN, ATF2 and kinases that bind and phosphorylate JUN on ELK1. neurites and decreased astrogliosis in a simi- S63 and Se73 within its transcriptional activa- JNKs are play a central role in the inflamma- lar study.33 Likewise, this inhibitor rescued tion domain. The deregulation of these kinas- tory signaling system, and thus it is not unex- neuronal apoptosis in the developing rat brain es is shown to be involved in human diseases, pected that deactivation of JNK signaling is after hypoxia-ischemia.34 AS601245 also such as cancer, immune diseases and neu- very common in a number of diseases, such as decreased cardiomyocyte apoptosis and infarct rodegenerative disorders. The realization of cancers, inflammatory, autoimmune and neu- size after myocardial ischemia and reperfu- the therapeutic potential of the inhibition of rodegenerative diseases. There’s plenty evi- sion in rat model of myocardial JNKs led to a thorough search for small-mole- dence showing that JNKs could be considered ischemia/reperfusion.35 cule inhibitors first for research purposes, but as therapeutic targets in Parkinson’s and Interesting findings have been obtained later also for therapeutic applications. Here, Alzheimer’s disease,19,20 obesity and insulin using AS601245 as an antiviral agent. we discuss some of the most well-known JNK resistance,21,22 rheumatoid arthritis,23 AS601245 as well as SP600125 inhibited cellu- inhibitors and their use in basic research or asthma,24-26 vascular disease and atherosclero- lar entry and replication of hepatitis C virus.36 clinical science. sis.27 In addition, the application of SP600125 and The importance of JNKs in many biological AS601245 reduced influenza A virus (H7N7 processes as well as pathologies led to a seri- and H1N1v) amplification by suppressing viral ous pursuit for small-molecule inhibitors, protein and RNA synthesis.37 AS601245 was Introduction which resulted in various small molecules also found to be a potent inhibitor of HIV-1 such as aminopyrazoles, aminopyridines, reactivation in latently infected primary T cells Protein kinases are a large family of aminopyrimidines, indazoles, pyridine carbox- and T cell lines.38 enzymes, which catalyze protein phosphoryla- amides, benzothien-2-ylamides and benzothia- Probably the most interesting are the find- tion. The phosphorylation of proteins results in zol-2-yl acetonitriles to be reported as JNK ings of AS601245 as an anticancer agent. a change in localization of protein and/or their inhibitors.28 Here we will discuss most inter- AS601245 decreased cell adhesion and migra- function such as interaction with other pro- esting and successful of those. tion via decrease in the fibrinogen release in teins, affinity or enzymatic activity.Non The commercial use humanonly colon cancer cells.39 It has also affected human genome contains more than 510 pro- the proliferation of colon cancer cell lines.40 tein kinase genes. Protein phosphorylation AS601245 also led T-cell acute lymphoblastic plays a crucial role in the regulation of many JNK inhibitors leukemia cells to cell cycle arrest and apoptosis cellular functions such as proliferation, differ- and increased sensitivity to Fas-mediated entiation, migration and apoptosis. Because of AS601245 is a potent and cell permeable ATP apoptosis41 and sensitized promonocytic that, deregulation of kinase activity can result competitive JNK inhibitor. IC50: JNK1 = leukemia cells to arsenic trioxide-induced in outstanding alterations in these processes. 150nM, JNK2 = 220nM, JNK3 = 70 nM (Figure apoptosis.42 For example, deregulated kinases are fre- 1). Displays anti-inflammatory properties as AS602801 (Bentamapimod) is a selective quently found to be oncogenic and can be shown in an experimental mouse model of JNK inhibitor that has been found to block T- essential for the survival of cancer cells.1 rheumatoid arthritis29 and has been shown to cell proliferation and induce apoptosis. IC50: Moreover, the phosphorylation of some pro- reduce TNF- plasma levels induced by LPS in JNK1 = 80 nM, JNK2 = 90 nM, JNK3 = 230 nM teins, such as ErbB2,2-4 EGFR,3,5 Erk,6-8 SchA,9 mice.30,31 It has also been shown to provide sig- (Figure 1). This inhibitor blocked T-lympho- Akt10,11 and many more, is associated with nificant protection against the loss of hip- cyte proliferation and induced apoptosis in prognosis in a number of human cancers. pocampal CA1 neurons in a gerbil model of relapsing-remitting multiple sclerosis c-Jun N-terminal kinases (JNKs) are mem- transient global ischemia, suggesting that it patients.43 In addition, it has been shown to bers of subfamily of MAP kinase family of ser- may be a pertinent approach in the therapy of induce the regression of endometriotic lesions ine/threonine kinases which are found in both ischemic insults,32 it also reduced damage to in human endometrial organ cultures, nude [MAP Kinase 2015; 4:5700] [page 31] Editorial mice xenograft as well as rat disease models.44 oxidative stress in rats,62 prevent the disrup- nM) (Figure 2).80 Pre-treatment of human AEG 3482 is a JNK inhibitor with an IC50 = 20 tion of blood-brain barrier induced by metham- astrocytes with either SP600125 or SU 3327, 63 μM (Figure 1). The action is not direct, since it phetamine and diminish neuronal cell death and trauma-induced human astrocyte retrac- binds Hsp90 and facilitates HSF1 release, in experimental cerebral malaria in mice.64 tion in in vitro study.81 Inhibition of JNK by induces expression of Hsp70, which in turn Worth mentioning is anticancer activity of SU3327 was shown to aggravate the recovery blocks JNK activation. It also reduces apoptosis SP600125 as well. It was shown to induce cell of rat hearts after global ischemia.82 SU 3327 of neonatal sympathetic neurons after NGF with- death selectively in undifferentiated thyroid was also shown to reduced mitochondrial dys- drawal.45 It was also shown to decrease neuron cancer cell lines,65 sensitize the multidrug- function and liver damage in acute liver injury 46 83 specific toxicity of oligomeric amyloid b. resistant KBV20C human oral squamous carci- mouse model. 66 BI 78D3 is a JNK inhibitor with an IC50 = noma cell line, enhance TGF--induced apop- 280 nM. It displays >100 fold selectivity over tosis of human cholangiocarcinoma cell line p38 kinases and no activity towards mTOR and RBE,67 suppress glioblastoma cells,68 selective- PI-3K (Figure 1). BI 78D3 acts via inhibition of ly kill p53-deficient human colon carcinoma Tanzisertib (CC-930) and D- JIP1-JNK binding. It has also been shown to cells in mouse xenograft model,69 enhance JNKI-1 (XG-102, AM-111) - restores insulin sensitivity in mouse disease dihydroartemisinin-induced apoptosis in First JNK inhibitors in clinical models of type 2 diabetes.47 BI-78D3 as well as human lung adenocarcinoma cells70 and SP600125 reduced phenylephrine- and nora- reduce the viability of doxorubicin resistant trials drenaline-induced contractions of human stomach cancer cells.71 Inflammation is anoth- prostate smooth muscle.48 Interestingly, BI- er area where SP600125 has been extensively Tanzisertib (CC-930) is a potent, selective, 78D3 pretreatment sensitized osteosarcoma studied. It was shown to have protective effects and orally active JNK inhibitor, developed by in an experimental model of cerulein-induced cells (but not normal osteoblasts) to doxoru- Cellgene company, with IC50: JNK1 = 0.06 μM, 49 pancreatitis,72 diet-induced rat model of non- bicin-induced apoptosis, which gives some JNK2 = 0.007 μM and JNK3 = 0.006 μM and ground for thoughts regarding the future com- alcoholic steatohepatitis73 and mouse model of selective against MAP kinases ERK1 and p38 allergic airway inflammation74 and promote 84 bination treatment. with IC50 of 0.48 and 3.4 μM respectively. Of CC-401 is a specific inhibitor of JNK with resolution of allergic airway inflammation in a panel of 240 kinases, EGFR was the only non- murine acute asthma model.75 In addition, IC50 = 25-50nM.