Inhibitors Targeting RIPK1/RIPK3: Old and New Drugs

Most RIPK1/3 kinase inhibitors designed to date are type II or type III kinase inhibitors, covering specific RIPK1 inhibitors, such as Nec-1s, GSK’772, GSK’547, and compound 22. Several existing multitargeting tyrosine kinase inhibitors, such as sorafenib, ponatinib, and pazopanib, show strong RIPK1 off-target effects. Kinase-independent, RIPK1-scaffold-mediated cell survival is (in)directly regulated by TAK1, IKK, MK2, and TBK1-dependent phosphorylation, implying that tyrosine kinase inhibitors that block these kinases may be not only advantageous in sensitizing cell death in cancer cells, but also disadvantageous in sensitizing RIPK1-mediated cell death, which may enhance barrier loss, infection, and inflammation. Some RIPK1 inhibitors are now in clinical trials for the treatment of rheumatoid arthritis, ulcerative colitis, and psoriasis, similar to anti-TNF (tumor necrosis factor) blocking strategies. It is thought that RIPK1 kinase inhibitors could form an alternative treatment for patients who are nonresponders or show adverse effects to anti-TNF treatment. The scaffolding function of receptor-interacting protein kinase 1 (RIPK1) regulates prosurvival signaling and inflammatory gene expression, while its kinase activity mediates both apoptosis and necroptosis; the latter involving RIPK3 kinase activity. The mutual transition between the scaffold and kinase functions of RIPK1 is regulated by (de)ubiquitylation and (de)phosphorylation. RIPK1-mediated cell death leads to disruption of epithelial barriers and/or release of damage-associated molecular patterns (DAMPs), cytokines, and chemokines, propagating inflammatory and degenerative diseases. Many drug development programs have pursued targeting RIPK1, and to a lesser extent RIPK3 kinase activity. In this review, we classify existing and novel small-molecule drugs based on their pharmacodynamic (PD) type I, II, and III binding mode. Finally, we discuss their applicability and therapeutic potential in inflammatory and degenerative experimental disease models. The scaffolding function of receptor-interacting protein kinase 1 (RIPK1) regulates prosurvival signaling and inflammatory gene expression, while its kinase activity mediates both apoptosis and necroptosis; the latter involving RIPK3 kinase activity. The mutual transition between the scaffold and kinase functions of RIPK1 is regulated by (de)ubiquitylation and (de)phosphorylation. RIPK1-mediated cell death leads to disruption of epithelial barriers and/or release of damage-associated molecular patterns (DAMPs), cytokines, and chemokines, propagating inflammatory and degenerative diseases. Many drug development programs have pursued targeting RIPK1, and to a lesser extent RIPK3 kinase activity. In this review, we classify existing and novel small-molecule drugs based on their pharmacodynamic (PD) type I, II, and III binding mode. Finally, we discuss their applicability and therapeutic potential in inflammatory and degenerative experimental disease models. interaction that alters enzymatic activity due to binding of effector molecule to an enzyme at site another than its active site. cysteine aspartic acid-specific protease that executes programmed apoptotic cell death. conserved amino acid motif (Asp-Phe-Gly) located at the beginning of the activation loop of protein kinases and that regulates kinase activity. transcription factor regulating cytokine production, immune responses, and cell survival. form of programmed necrotic or inflammatory cell death. Necroptosis is executed by mixed-lineage kinase domain-like pseudokinase (MLKL), which translocates to cell membranes upon activation and permeabilizes the plasma membrane, which leads to rupture of the cell. enzyme that can transfer a phosphate group from ATP to its target molecules (proteins), also called phosphorylation, thereby modifying the behavior of the target. study of how a drug is processed by an organism. This includes absorption, distribution, metabolism, excretion (ADME) studies. study of the biological and physiological effects of a drug on an organism. modulators of cell survival, cell death, and inflammation. domain in RIP kinases that mediates protein–protein interactions with other RHIM domain-containing proteins (ZBP1 and TRIF). It is an important domain for virus recognition. analysis of the relationship between the chemical structures of a molecule and its biological activity. environment surrounding tumor cells, including blood vessels, immune cells, fibroblasts, extracellular matrix, and signaling molecules. process of adding ubiquitin to a target protein at a lysine residue. Sequential activation of ubiquitin-activating enzymes (E1), ubiquitin-conjugating enzymes (E2), and ubiquitin ligases (E3) is needed for this process. recognizes Z-DNA or Z-RNA in the cytoplasm as an antiviral mechanism.