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Targeting JNK for therapeutic benefit: from junk to gold?

Nature Reviews Drug Discovery volume 2, pages 554–565 (2003)Cite this article

Key Points

  • The c-Jun NH2-terminal kinases (JNKs) phosphorylate and activate members of the activator protein-1 (AP-1) transcription factor family and other cellular factors implicated in regulating altered gene expression, cellular survival and proliferation in response to cytokines and growth factors, to noxious stimuli and to oncogenic transformation. Because these events are commonly associated with the pathogenesis of a number of human diseases, the potential of JNK inhibitors as therapeutics has attracted considerable interest.

  • Activated immune cells express many genes encoding inflammatory molecules, including cytokines, growth factors, cell surface receptors, cell adhesion molecules and degradative enzymes. Many of these genes are regulated by the JNK pathway, through activation of the transcription factors AP-1 and ATF-2. JNK's represent attractive targets for immunomodulatory drug development.

  • Neurodegenerative diseases, including Alzheimer's, Parkinson's and Huntington's diseases, and stroke, share synaptic loss, neuronal atrophy and death as pathological hallmarks. JNK plays an integral role in neuronal death and this pathway might be operative in various central nervous system disease states.

  • Obesity and type 2 diabetes are the most prevalent and serious of the metabolic diseases. Insulin resistance is closely associated with these syndromes, and is commonly seen in hypertension, and following infection and injury. Mice lacking JNK1 displayed decreased adiposity, significantly improved insulin sensitivity and enhanced insulin receptor signalling in the high-fat and ob/ob models, suggesting JNK as a target for preventing insulin resistance.

  • A substantial body of evidence suggests that JNK activation and c-Jun phosphorylation are required for transformation induced by Ras, an oncogene that is mutationally activated in almost 30% of human cancers. JNK also seems to play a significant role in tumour development, although in certain cases this role might be to promote or inhibit tumour development.

  • The combination of high-throughput screening, kinase-specific libraries and structure-based drug design has facilitated the discovery of selective JNK inhibitors. Determination of the X-ray structure of the members of the mitogen-activated protein kinase family, extracellular signal-regulated kinase, p38 and JNK3 has aided the design of potent yet selective inhibitors of the JNKs. These efforts have led to the patenting of a series of JNK inhibitors.

Abstract

The c-Jun NH2-terminal kinases (JNKs) phosphorylate and activate members of the activator protein-1 (AP-1) transcription factor family and other cellular factors implicated in regulating altered gene expression, cellular survival and proliferation in response to cytokines and growth factors, noxious stimuli and oncogenic transformation. Because these events are commonly associated with the pathogenesis of a number of human diseases, the potential of JNK inhibitors as therapeutics has attracted considerable interest. Here we discuss the evidence supporting the application of JNK inhibitors in inflammatory, vascular, neurodegenerative, metabolic and oncological diseases in humans, and describe the present status of drug discovery targeting JNK.

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Figure 1: Structural features of the JNK proteins.
Figure 2: Organization of the JNK signal transduction cascade.
Figure 3: Modular organization of JNK signalling complexes.
Figure 4: Inflammatory gene expression and JNKs.
Figure 5: Biological functions of JNK.
Figure 6: Inhibitors of JNKs reported in the patent literature.

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Acknowledgements

Special thanks to A. Lewis and B. Bennett at the Signal Research Division of Celgene for permission to reproduce Figs 3 and 5.

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Authors and Affiliations

  1. Roche Pharmaceuticals, 3411 Hillview Avenue, Palo Alto, 94306, CA, USA

    Anthony M. Manning

  2. Howard Hughes Medical Institute, University of Massachusetts Medical School, 373 Plantation Street, Suite 306, Worcester, 01605, MA, USA

    Roger J. Davis

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DATABASES

LocusLink

APP

CDK5/p35

E-selectin

GSK3β

IL-2

JNK1

JNK2

JNK3

MAP2K4

MAP2K7

MAPK3

MMP3

MMP9

MMP13

PSEN1

PSEN2

TNF-α

Online Mendelian Inheritance in Man

Asthma

Inflammatory bowel disease

Multiple sclerosis

Psoriasis

Rheumatoid arthritis

Glossary

AP-1 TRANSCRIPTION FACTOR

The transcription factor AP-1 is composed of homo- or hetero-dimers of proteins that belong to the FOS and JUN families. JUN proteins can homo-dimerize, but FOS proteins can only form stable dimers with JUN. AP-1 dimers can be phosphorylated by JNK and other MAP kinases and hence develop an enhanced DNA-binding capacity and transcriptional activity.

IC50

The concentration of drug at which activity of a particular assay is inhibited by 50%. This is a typically used value to describe the relative potency of a drug agent.

NEUROFIBRILLARY TANGLES

Intracellular aggregates of paired helical filaments composed primarily of hyper-phosphorylated Tau proteins. Tau is a microtubule-associated protein found within neurons and normally restricted to axons. Hyper-phosphorylated Tau forms tangled masses that consume the neuronal cell body, presumably leading to neuronal dysfunction and ultimately cell death.

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Manning, A., Davis, R. Targeting JNK for therapeutic benefit: from junk to gold?. Nat Rev Drug Discov 2, 554–565 (2003). https://doi.org/10.1038/nrd1132

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