Inhibitors Targeting RIPK1/RIPK3: Old and New Drugs. (March 2020) - Martens, Sofie
Abstract : 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. Highlights: 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.