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Review
. 2020 Mar;98(3):335-348.
doi: 10.1007/s00109-020-01878-y. Epub 2020 Feb 14.

ASK1 Inhibition: A Therapeutic Strategy With Multi-System Benefits

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Free PMC article
Review

ASK1 Inhibition: A Therapeutic Strategy With Multi-System Benefits

Jacqueline M Ogier et al. J Mol Med (Berl). .
Free PMC article

Abstract

p38 mitogen-activated protein kinases (P38α and β) and c-Jun N-terminal kinases (JNK1, 2, and 3) are key mediators of the cellular stress response. However, prolonged P38 and JNK signalling is associated with damaging inflammatory responses, reactive oxygen species-induced cell death, and fibrosis in multiple tissues, such as the kidney, liver, central nervous system, and cardiopulmonary systems. These responses are associated with many human diseases, including arthritis, dementia, and multiple organ dysfunctions. Attempts to prevent P38- and JNK-mediated disease using small molecule inhibitors of P38 or JNK have generally been unsuccessful. However, apoptosis signal-regulating kinase 1 (ASK1), an upstream regulator of P38 and JNK, has emerged as an alternative drug target for limiting P38- and JNK-mediated disease. Within this review, we compile the evidence that ASK1 mediates damaging cellular responses via prolonged P38 or JNK activation. We discuss the potential benefits of ASK1 inhibition as a therapeutic and summarise the studies that have tested the effects of ASK1 inhibition in cell and animal disease models, in addition to human clinical trials for a variety of disorders.

Keywords: Apoptosis signal-regulating kinase 1; Clinical trial; JNK; MAP3K5; MAPK; ROS; p38.

Conflict of interest statement

The authors declare that they have no conflict of interest.

Figures

Fig. 1
Fig. 1
In the redox neutral cell, dithiol oxidoreductases TRX, GRX, and PRX bind to and inactivate ASK1. However, cell stressors can induce cellular oxidative imbalance, which causes disulphide bonds to form between the cysteine residues of TRX, GRX, or PRX. As a result, TRX, PRX, and GRX dissociate from ASK1. Unbound ASK1 is then activated by auto-phosphorylation and a large multicomponent complex forms, referred to as the ASK1 signalosome. The ASK1 signalosome promotes the sustained activation of the P38 and JNK signalling cascades which have been associated with damaging inflammatory responses, cell death, and fibrosis in multiple tissues

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