title: Generation of small molecules to interfere with regulated necrosis.
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.
authors.affiliation: Department of Developmental, Molecular & Chemical Biology, Sackler School of Graduate Biomedical Sciences, Tufts University School of Medicine, Boston, MA, 02111, USA. alexei.degterev@tufts.edu.
authors.forename: Alexei
authors.initials: A
authors.lastname: Degterev
authors.affiliation: Clinic for Nephrology and Hypertension, University-Hospital Schleswig-Holstein, Campus Kiel, Christian-Albrechts-University Kiel, Fleckenstr. 4, 24105, Kiel, Germany. andreas.linkermann@uksh.de.
authors.forename: Andreas
authors.initials: A
authors.lastname: Linkermann
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D003514:Cyclohexylamines / Q000494:pharmacology; D006576:Heterocyclic Compounds, 4 or More Rings / Q000494:pharmacology; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D051379:Mice; D009336:Necrosis / Q000188:drug therapy* / Q000473:pathology*; D009930:Organic Chemicals / Q000494:pharmacology; D010655:Phenylenediamines / Q000494:pharmacology; D011494:Protein Kinases / Q000378:metabolism*; D011724:Pyridazines / Q000494:pharmacology; D011810:Quinoxalines / Q000494:pharmacology; D053422:Receptor-Interacting Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D013141:Spiro Compounds / Q000494:pharmacology; D013450:Sulfones / Q000494:pharmacology
chemical_list: D003514:Cyclohexylamines; D006576:Heterocyclic Compounds, 4 or More Rings; D007093:Imidazoles; C574766:NecroX-5; D009930:Organic Chemicals; D010655:Phenylenediamines; D011724:Pyridazines; D011810:Quinoxalines; D013141:Spiro Compounds; D013450:Sulfones; C573944:ferrostatin-1; C000595890:liproxstatin-1; C556282:necrox-7; C545373:ponatinib; C570693:MLKL protein, human; D011494:Protein Kinases; C506249:RIPK1 protein, human; C119705:RIPK3 protein, human; D053422:Receptor-Interacting Protein Serine-Threonine Kinases
keywords: Ferroptosis; Ferrostatins; Necroptosis; Necrostatins; Programmed cell death; Regulated necrosis; TNF