Table 1 |.
Summary of small-molecule modulators of regulated necrotic cell death
| Compound name (alternative name) | Mechanism of action | Applications | Refs |
|---|---|---|---|
| RIPK1-dependent apoptosis | |||
| Necrostatin-1 | RIPK1 inhibitor | Protected mice and rats against neurodegenerative conditions (for example, TBI, stroke, HD and AD), retinal degeneration, inflammatory diseases (including sepsis, alcoholic or non-alcoholic liver diseases, pancreatitis and IBD) and microbial infections | 10,11,20 |
| Nec-1s (R-7-Cl-O-Nec-1) | RIPK1 inhibitor | Prevented TNF-induced lethality in a mouse model of SIRS | 37 |
| PN10 | RIPK1 inhibitor | Prevented TNF-induced lethality in a mouse model of SIRS | 42 |
| Cpd27 | RIPK1 inhibitor | Prevented TNF-induced lethality in a mouse model of SIRS | 41 |
| Necrosulfonamide | MLKL inhibitor | Prevented necroptosis induced by TNF plus Z-VAD-FMK in mouse fibroblasts | 49 |
| Necroptosis | |||
| GSKʹ840, GSKʹ843 and GSKʹ872 | RIPK3 inhibitors | Prevented LPS-induced death of mouse macrophages, cell death induced by TNF plus Z-VAD-FMK, and poly(I:C)-triggered death of interferon-β-sensitized cells in vitro | 33 |
| Compound 1 (SYN-1215 or GW806742X) | MLKL inhibitor | Inhibited necroptotic death of mouse dermal fibroblasts stimulated with a combination of caspase inhibitors, cIAP inhibitors and TNF | 34 |
| Inflammasome | |||
| MCC950 | NLRP3 inhibitor | Inhibited interleukin-1β production in vivo and attenuated the severity of EAE, a mouse model of multiple sclerosis | 151 |
| Parthanatos | |||
| MNNG | DNA-alkylating agent | Induced necrotic cell death through PARP overactivation | 182 |
| Benzamide | PARP inhibitor | Reduced neurodegeneration in a rat model of soman-induced seizure-related brain damage | 178,183 |
| Substituted benzamide derivatives; for example, INO-1001 (3-aminobenzamide) | Competitive PARP inhibitors | Widely used in various disease models, including TBI; reduced pulmonary injury and improved recovery of myocardial and endothelial function after hypothermic cardiac arrest; in a Phase II trial of INO-1001 in myocardial ischaemia, plasma from INO-1001-treated patients exhibited reduced in vitro PARP activity by >90% at all doses, with a trend towards blunting of inflammation | 112, 184–188 |
| 4-methoxyflavone | PARP inhibitor | Prevented cell death caused by the parthanatos-inducing DNA-alkylating agent MNNG | 179 |
| 3ʹ,4ʹ-dimethoxyflavone | PARP inhibitor | Prevented cell death caused by the parthanatos-inducing DNA-alkylating agent MNNG | 179 |
| PJ34 | PARP inhibitor | Reduced brain infarct size in a mouse model of transient focal ischaemia | 180 |
| DPQ | PARP inhibitor | Decreased cell death and prevented cardiac dysfunction after a non-lethal myocardial infarction in rats | 181 |
| Ferroptosis | |||
| Erastin | System Xc− inhibitor | Induced ferroptosis in diverse cell types | 56 |
| Piperazine erastin | System Xc− inhibitor | Reduced growth in a xenograft mouse tumour model (HT-1080 cells) | 60 |
| Erastin analogue 21 | System Xc− inhibitor | Induced ferroptosis in various cell types | 91 |
| Sorafenib | System Xc− inhibitor | Induced cell death in hepatocellular and renal cell carcinoma cell lines, as well as in other cancer cell lines | 91,93 |
| Liproxstatin-1 | Inhibits lipid peroxidation | Prevented Gpx4-knockout-induced acute renal failure and inhibited hepatic IRI in mice | 61 |
| Ferrostatin-1 | Inhibits lipid peroxidation | Prevented glutamate-induced neurotoxicity in cortical explants and IRI in a mouse model of kidney damage | 56,62 |
| Ferrostatin analogue SRS-11–92 | Inhibits lipid peroxidation | Efficacious in different cellular and slice models of HD, kidney tubule cell death and periventricular leukomalacia | 71 |
| Ferrostatin analogue SRS-16–86 | Inhibits lipid peroxidation | Inhibited tissue injury in a mouse model of renal IRI | 62 |
| (1S,3R)-RSL3 | GPX4 inhibitor | Reduced tumour growth in a mouse xenograft model | 60 |
| Altretamine | GPX4 inhibitor | Drug approved for use in ovarian cancer | 79 |
| Baicalein | LOX inhibitor | Protected against multiple degenerative disorders, including stroke | 157 |
| Ferroptosis (cont.) | |||
| LOXBlock-1 | LOX inhibitor | Reduced brain infarct size in a mouse model of transient focal ischaemia | 156 |
| LOXBlock-2 | LOX inhibitor | Protected a mouse hippocampal cell line from glutamate-induced oxytosis | 189 |
| LOXBlock-3 | LOX inhibitor | Protected a mouse hippocampal cell line from glutamate-induced oxytosis | 189 |
| α-tocopherol | Inhibits lipid peroxidation | In general, protects cells and tissues, particularly in the brain, muscles and blood cells. In the context of GPX4 deficiency, prevented thromboembolic events78 and impaired parasite infections and CD8+ T cell homeostasis77 | 190 |
| Compound 968 | Glutaminase inhibitor | Reduced infarct size after IRI in isolated hearts of mice | 85 |
| L-buthionine sulfoximine | γ-GCS inhibitor | Triggered glutathione depletion and GPX4 inhibition, and prevented malignant transformation | 191,192 |
| CypD-dependent or CypD-independent necrosis | |||
| Cyclosporin A | CypD inhibitor | Protective in several mouse and rat models of IRI in organs, such as retina, heart, brain and kidney | 115, 193–195 |
| Sanglifehrin A | CypD inhibitor | Protective in several mouse and rat models of IRI in organs, such as heart and kidney | 131,196 |
| Pifithrin-μ | Inhibits p53 translocation to mitochondria | Protected mice from gamma-radiation-induced lethal haematopoietic syndrome | 124,197 |
γ-GCS, γ-glutamylcysteine synthetase; AD; Alzheimer disease; baicalein, 5,6,7-trihydroxyflavone; cIAP, cellular inhibitor of apoptosis protein; CypD, cyclophilin D; DPQ, 3,4-dihydro-5[4-(1-piperindinyl)butoxy]-1(2H)-isoquinoline; EAE, experimental autoimmune encephalomyelitis; GPX4, glutathione peroxidase 4; HD, Huntington disease; IBD, inflammatory bowel disease; IRI, ischaemia–reperfusion injury; LOX, lipoxygenase; LPS, lipopolysaccharide; MLKL, mixed lineage kinase domain-like protein; MNNG, N-methyl-Nʹ-nitro-N-nitrosoguanidine; NLRP3, NOD-, LRR- and pyrin domain-containing 3; PARP, poly(ADP-ribose) polymerase; PJ34, N-(5,6-dihydro-6-oxo-2-phenanthridinyl)-2-acetamide hydrochloride); pol(I:C), polyinosinic-polycytidylic acid; RIPK, receptor-interacting protein kinase; SIRS, systemic inflammatory response syndrome; TBI, traumatic brain injury; TNF, tumour necrosis factor.