Finally, we summarize the current state of RIPK1 inhibitors in the clinic, including disease indications, small-molecule chemotypes, as well as RIPK1 target engagement and pharmacodynamic biomarkers. We postulate that the improved understanding of genetic and mechanistic data may be beneficial in segmenting patients in clinical trials, particularly for neurodegenerative and inflammatory diseases. The involvement of RIPK1 in sepsis and acute ischaemic conditions is also discussed. In this Review, we outline the current understanding of RIPK1 biology in activating cell death and NF-κB signalling, systematically review monogenic and polygenic variants of known RIPK1 regulators and discuss how these mutations may contribute to disease pathology. The important role of RIPK1 in driving cell death and inflammation, the established safety of inhibiting RIPK1 kinase activity in humans and the ability to develop selective small-molecule kinase inhibitors of RIPK1 due to the presence of a unique kinase-regulating allosteric pocket are the major factors that have contributed to RIPK1’s prominence as a therapeutic target. These trials have laid the groundwork for advancing clinical applications of RIPK1 inhibitors. The brain-penetrant DNL747 is in human clinical trial phase Ib/IIa for amyotrophic lateral sclerosis (ALS) 15, 16. The peripherally restricted GSK′772 is being developed for peripheral autoimmune diseases, including psoriasis, rheumatoid arthritis (RA) and ulcerative colitis 12, 13, 14. Broad therapeutic applications of RIPK1 inhibitors for the treatment of a wide range of human diseases are being investigated in clinical trials. Necrostatin-1s (Nec-1s) was the first small-molecule inhibitor of RIPK1 kinase to be developed and has been widely used to investigate the role of RIPK1 in mechanistic studies and animal models of human diseases 1, 8, 9, 10, 11. However, as researchers continued to delve into the mechanisms governed by RIPK1, it has become apparent that RIPK1 inhibitors may offer key therapeutic options that anti-TNF therapies do not: first, RIPK1 inhibitors are safe in the central nervous system (CNS) as RIPK1 kinase does not signal through TNFR2 which has a protective role in the CNS 7 second, RIPK1 participates in a broader set of pro-inflammatory activities than those restricted to TNF 8 third, RIPK1 is regulated by a distinct set of signalling molecules that are genetically implicated in human autoimmune and autoinflammatory diseases, as discussed below, and thus patient stratification may be important in conducting clinical trials of RIPK1 inhibitors. As TNFR1-mediated RIPK1 activation is the most comprehensively characterized paradigm, RIPK1 inhibitors were originally considered to primarily offer a small-molecule alternative to anti- TNF antibody therapies for TNF-driven autoimmune conditions. RIPK1 kinase activation has been demonstrated in post-mortem human pathological samples of autoimmune and neurodegenerative conditions 3, 4, 5, 6, and inhibition of RIPK1 kinase activity has shown efficacy in a wide range of animal models of human diseases. Receptor-interacting serine/threonine-protein kinase 1 (RIPK1) is a master regulator of the cellular decision between pro-survival NF-κB signalling and death in response to a broad set of inflammatory and pro-death stimuli in human diseases 1, 2.
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