P38 mitogen-activated protein kinases

Clinical significance

Oxidative stress is the most powerfully specific stress activating p38 MAPK. Abnormal activity (higher or lower than physiological) of p38 has been implicated in pathological stresses in several tissues, that include neuronal, bone, lung, cardiac and skeletal muscle, red blood cells, and fetal tissues. The protein product of proto-oncogene RAS can increase activity of p38, and thereby cause excessively high activity of transcription factor NF-κB. This transcription factor is normally regulated from intracellular pathways that integrate signals from the surrounding tissue and the immune system. In turn these signals coordinate between cell survival and cell death. Dysregulated NF-κB activity can activate genes that cause cancer cell survival, and can also activate genes that facilitate cancer cell metastasis to other tissues. P38 was also shown to correlate with outcome of glioblastoma - higher pathway activity is associated with low survival.

Inhibitors

p38 inhibitors are being sought for possible therapeutic effect on autoimmune diseases and inflammatory processes, e.g. pamapimod. Some have started clinical trials, e.g. PH-797804 for COPD. Other p38 inhibitors include BIRB 796, VX-702, SB239063, SB202190, SB203580, SCIO 469, and BMS 582949.

As of 2020, losmapimod, a p38 inhibitor, is being investigated for the treatment of facioscapulohumeral muscular dystrophy (FSHD) on the basis of p38 inhibition inhibiting the effects of DUX4.

References

References

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2. (2016). "Regulation of Muscle Stem Cell Functions: A Focus on the p38 MAPK Signaling Pathway". Frontiers in Cell and Developmental Biology.
3. (August 1994). "A MAP kinase targeted by endotoxin and hyperosmolarity in mammalian cells". Science.
4. (July 2000). "ERKs and p38 kinase phosphorylate p53 protein at serine 15 in response to UV radiation". Journal of Biological Chemistry.
5. (June 2009). "The p38 MAPK pathway inhibits tristetraprolin-directed decay of interleukin-10 and pro-inflammatory mediator mRNAs in murine macrophages". FEBS Letters.
6. (2014). "The MAP Kinase p38 Is Part of Drosophila melanogaster's Circadian Clock". PLOS Genetics.
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13. (June 2016). "The Role of p38 MAPK in the Development of Diabetic Cardiomyopathy". International Journal of Molecular Sciences.
14. (August 2016). "Regulation of Muscle Stem Cell Functions: A Focus on the p38 MAPK Signaling Pathway". Frontiers in Cell and Developmental Biology.
15. (October 2017). "Suicidal death of erythrocytes in cancer and its chemotherapy: A potential target in the treatment of tumor-associated anemia". International Journal of Cancer.
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18. (2013-04-11). "hsa-miR-9 and drug control over the P38 network as driving disease outcome in GBM patients". Systems Biomedicine.
19. (2005). "Pathway to the clinic: inhibition of P38 MAP kinase. A review of ten chemotypes selected for development". Current Topics in Medicinal Chemistry.
20. (December 2008). "Pamapimod, a novel p38 mitogen-activated protein kinase inhibitor: preclinical analysis of efficacy and selectivity". The Journal of Pharmacology and Experimental Therapeutics.
21. (2010). "Novel p38 Inhibitor Shows Promise as Anti-Inflammatory Treatment for Patients With COPD".
22. (October 2019). "O.25Phase 1 clinical trial of losmapimod in FSHD: safety, tolerability and target engagement". Neuromuscular Disorders.