The c-Jun N-terminal kinases (JNKs) are members of a larger group of serine/threonine (Ser/Thr) protein kinases from the mitogen-activated protein kinase family. It has 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.

c-Jun N-terminal protein kinase (JNK) was originally identified as two protein kinases of p46JNK1 and p54JNK2, which specifically phosphorylate the transcription factor c-Jun on its N-terminal transactivation domain at Ser63 and Ser73. This phosphorylation can be induced by a variety of extracellular stimuli, resulting in the augmentation of c-Jun transcriptional activity and its ability to cooperate with Ha-Ras in transformation. Thus, JNK is a key regulator of c-Jun activity. Molecular cloning of JNK (also known as stress-activated protein kinase (SAPK) revealed that it is a member of the (anthra[1,9-cd]pyrazol-6(2H)-one) from Signal Pharmaceuticals/Celgene, an ATP competitive inhibitor of JNK1, 2 and 3 with a Ki of 100-200 nM. The advantages of this compound were its specificity of action and its selectivity against the related MAP kinases ERK and p38. Consequently SP600125 has been used as a pharmacologic tool in over 300 journal articles. Consistent with knock-out and biochemical studies, SP600125 has been shown to inhibit endotoxin induced TNFα expression, suppress bone degeneration in models of arthritis, inhibit acute T-cell inflammation and liver injury, decrease allergen induced airway inflammation and remodeling enhance survival of dopaminergic neurons in the MPTP model, and protect from ischemia-reperfusion injury. However, SP600125 does inhibit multiple other protein kinases, may have additional cell activity, and lacks the physical chemical properties required of a clinical compound.

At the American Chemical Society meeting in 2003, Serono described a novel benzothiazol-2-yl acetonitrile derivative JNK inhibitor, , a second generation JNK inhibitor for autoimmune and inflammatory conditions.

The first small molecule inhibitor of JNK to enter clinical trials was CC-401 (Celgene). A corporate press release dated February 5, 2003 stated CC-401, “successfully completed a Phase I, double-blind, placebo controlled, ascending single intravenous dose study in healthy human Volunteers”, a statement which while lacking in detail does provide some preliminary evidence that acute toxicity may not be an issue with JNK inhibitors. Neither a chemical structure or a detailed characterization of this compound has been publicly disclosed although its hepatocyte protecting activity in a model of rat liver transplant has been described. In these studies CC-401 was found to be most efficacious when present in the liver prior to reperfusion that follows surgical implantation. This is consistent with the dogma that it is the reperfusion event that leads to rapid induction of JNK activity in hepatocytes. It was also observed that CC-401 inhibited cytoplasmic cytochrome c providing confirmatory evidence that JNK does play a role in the mitochondria dependent apoptosis pathway, at least in settings of oxidative injury to the cell. It is interesting to note that the initial efficacy data for AS601245 and CC-401 have independently focused on the area of cellular apoptosis caused by ischemic or ischemia-reperfusion injury suggesting this may be a promising clinical development route for JNK inhibitors.

The identification and development of JNK inhibitors as therapeutics is a competitive arena and numerous chemical classes of JNK inhibitors have been disclosed in patent applications, mostly from pharmaceutical companies. As much of this work is proprietary it is possible that one or more JNK inhibitors representative of these classes are also in clinical trials.


Lin, A. (2003). Activation of the JNK signaling pathway: breaking the brake on apoptosis. Bioessays, 25(1), 17-24.

The JNK Signaling Pathway. Anning Lin

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