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Generation of small molecules to interfere with regulated necrosis

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Abstract

Interference with regulated necrosis for clinical purposes carries broad therapeutic relevance and, if successfully achieved, has a potential to revolutionize everyday clinical routine. Necrosis was interpreted as something that no clinician might ever be able to prevent due to the unregulated nature of this form of cell death. However, given our growing understanding of the existence of regulated forms of necrosis and the roles of key enzymes of these pathways, e.g., kinases, peroxidases, etc., the possibility emerges to identify efficient and selective small molecule inhibitors of pathologic necrosis. Here, we review the published literature on small molecule inhibition of regulated necrosis and provide an outlook on how combination therapy may be most effective in treatment of necrosis-associated clinical situations like stroke, myocardial infarction, sepsis, cancer and solid organ transplantation.

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Acknowledgments

A.D. is supported by National Institute of General Medical Sciences grants R01GM080356 and R01GM084205. Research by A.L. is funded by the German Research Foundation, Cluster of Excellence EXC306.

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  1. Department of Developmental, Molecular & Chemical Biology, Sackler School of Graduate Biomedical Sciences, Tufts University School of Medicine, Boston, MA, 02111, USA

    Alexei Degterev

  2. Clinic for Nephrology and Hypertension, University-Hospital Schleswig-Holstein, Campus Kiel, Christian-Albrechts-University Kiel, Fleckenstr. 4, 24105, Kiel, Germany

    Andreas Linkermann

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Degterev, A., Linkermann, A. Generation of small molecules to interfere with regulated necrosis. Cell. Mol. Life Sci. 73, 2251–2267 (2016). https://doi.org/10.1007/s00018-016-2198-x

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