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Interacting Protein Kinase 1 (RIPK1) As a Therapeutic Target

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Interacting Protein Kinase 1 (RIPK1) As a Therapeutic Target REVIEWS Receptor- interacting protein kinase 1 (RIPK1) as a therapeutic target Lauren Mifflin 1, Dimitry Ofengeim2 and Junying Yuan 1 ✉ Abstract | Receptor-interacting serine/threonine- protein kinase 1 (RIPK1) is a key mediator of cell death and inflammation. The unique hydrophobic pocket in the allosteric regulatory domain of RIPK1 has enabled the development of highly selective small-molecule inhibitors of its kinase activity, which have demonstrated safety in preclinical models and clinical trials. Potential applications of these RIPK1 inhibitors for the treatment of monogenic and polygenic autoimmune, inflammatory, neurodegenerative, ischaemic and acute conditions, such as sepsis, are emerging. This article reviews RIPK1 biology and disease- associated mutations in RIPK1 signalling pathways, highlighting clinical trials of RIPK1 inhibitors and potential strategies to mitigate development challenges. NF-κ B Receptor-interacting serine/threonine-protein kinase 1 peripherally restricted GSK′772 is being developed for (Nuclear factor κ light chain (RIPK1) is a master regulator of the cellular decision peripheral autoimmune diseases, including psoriasis, enhancer of activated B cells). between pro- survival NF- κB signalling and death in rheumatoid arthritis (RA) and ulcerative colitis12–14. A protein complex whose response to a broad set of inflammatory and pro-death The brain- penetrant DNL747 is in human clinical trial pathway, which can be 1,2 15,16 activated in response to stimuli in human diseases . RIPK1 kinase activation phase Ib/IIa for amyotrophic lateral sclerosis (ALS) . cytokines, free radicals, viral or has been demonstrated in post- mortem human patho- These trials have laid the groundwork for advancing bacterial antigens and other logical samples of autoimmune and neurodegenerative clinical applications of RIPK1 inhibitors. stressors, mediates the conditions3–6, and inhibition of RIPK1 kinase activity The important role of RIPK1 in driving cell death transcription of genes has shown efficacy in a wide range of animal models and inflammation, the established safety of inhibiting required for pro- survival and TNFR1 pro- inflammatory signalling. of human diseases. As - mediated RIPK1 activa- RIPK1 kinase activity in humans and the ability to tion is the most comprehensively characterized para- develop selective small- molecule kinase inhibitors of TNFR1 digm, RIPK1 inhibitors were originally considered to RIPK1 due to the presence of a unique kinase-regulating (Tumour necrosis factor primarily offer a small- molecule alternative to anti- TNF allosteric pocket are the major factors that have contrib- receptor 1). A type I membrane receptor that antibody therapies for TNF-driven autoimmune condi- uted to RIPK1’s prominence as a therapeutic target. In contains an intracellular death tions. However, as researchers continued to delve into this Review, we outline the current understanding of domain that, when activated, the mechanisms governed by RIPK1, it has become RIPK1 biology in activating cell death and NF- κB sig- can recruit receptor- interacting apparent that RIPK1 inhibitors may offer key therapeu- nalling, systematically review monogenic and polygenic serine/threonine- protein tic options that anti- TNF therapies do not: first, RIPK1 variants of known RIPK1 regulators and discuss how kinase 1 (RIPK1) and TRADD to mediate inflammatory and inhibitors are safe in the central nervous system (CNS) these mutations may contribute to disease pathology. pro- survival functions through as RIPK1 kinase does not signal through TNFR2 which The involvement of RIPK1 in sepsis and acute ischae- the NF-κ B pathway, as well as has a protective role in the CNS7; second, RIPK1 par- mic conditions is also discussed. We postulate that the cell death mediated by RIPK1 ticipates in a broader set of pro- inflammatory activities improved understanding of genetic and mechanistic kinase activity. than those restricted to TNF8; third, RIPK1 is regulated data may be beneficial in segmenting patients in clinical by a distinct set of signalling molecules that are geneti- trials, particularly for neurodegenerative and inflamma- cally implicated in human autoimmune and autoinflam- tory diseases. Finally, we summarize the current state of matory diseases, as discussed below, and thus patient RIPK1 inhibitors in the clinic, including disease indi- 1Department of Cell Biology, stratification may be important in conducting clinical cations, small- molecule chemotypes, as well as RIPK1 Harvard Medical School, trials of RIPK1 inhibitors. target engagement and pharmacodynamic biomarkers. Boston, MA, USA. Necrostatin-1s (Nec-1s) was the first small-molecule 2 Rare and Neurologic inhibitor of RIPK1 kinase to be developed and has Distinct kinase and scaffold functions of RIPK1 Disease Research, Sanofi, Framingham, MA, USA. been widely used to investigate the role of RIPK1 in RIPK1 is a 76- kDa protein with an amino- terminal ✉e- mail: junying_yuan@ mechanistic studies and animal models of human (N- terminal) kinase domain, a carboxy- terminal 1,8–11 hms.harvard.edu diseases . Broad therapeutic applications of RIPK1 (C- terminal) death domain and an intermediate https://doi.org/10.1038/ inhibitors for the treatment of a wide range of human domain with a RHIM (receptor- interacting protein s41573-020-0071- y diseases are being investigated in clinical trials. The homotypic interacting motif) that can bind to other NATURE REVIEWS | DRUG DISCOVERY VOLUME 19 | AUGUST 2020 | 553 REVIEWS 2,17 TNF RHIM- containing proteins . Whereas the C- terminal activation, which in turn determines the mode of cell (Tumour necrosis factor). death domain mediates homodimerization as well as death. There is an extensive body of literature identifying A pro- inflammatory cytokine heterodimerization with other death domain-containing cell type- specific roles for RIPK1 activity using condi- typically secreted by proteins, such as FADD, TNFR1 and Fas, the N-terminal tional mouse models that we and others have summa- macrophages/monocytes and microglia. TNF signals through kinase domain mediates autophosphorylation in trans rized previously, and so do not cover in detail in this 18,19 1,2 two receptors: TNFR1, which to promote its own activation . The scaffold function article . For example, in certain cell types, such as oligo- mediates cell death and NF- κB of RIPK1 is essential for mediating pro-survival NF- κB dendrocytes, TNF stimulation alone may promote the signalling; and TNFR2, which signalling and mouse perinatal survival: Ripk1–/– mice activation of RIPK1 and cell death3,4; in other cell types, mediates non- canonical NF-κ B are born normally but die at postnatal day 1–3 (REF.20). such as fibroblasts, sustained activation of RIPK1 kinase signalling. RIPK1 deficiency reduces NF- κB- mediated transcrip- can only be achieved when TNF stimulation is combined Complex I tion of pro- survival proteins, such as cellular FLICE- with chemical inactivators of RIPK1 repressors, such as A transient complex associated like inhibitory protein (cFLIP), cIAP1 and A20 (REF.21). cIAP1/2 (inhibited by SM-164), TAK1, TBK1 or IKKs, with the intracellular domain of The perinatal lethality of Ripk1–/– mice can be rescued that are both mediators of the NF- κB pathway and TNFR1 upon TNF stimulation 18,33–35 that includes RIPK1 and many by inhibition of both apoptotic and regulated necrotic inhibitors of RIPK1 kinase activation . –/– –/– –/– other regulators of NF-κ B cell death (necroptosis) in Ripk1 Fadd Ripk3 , Ubiquitylation of RIPK1 in complex I, which is organ- activation and cell death. Ripk1–/–Casp8–/–Ripk3–/– or Ripk1–/–Fadd–/–Mlkl–/– ized by TRADD, is essential for suppressing the aberrant mice22–26. activation of RIPK1 kinase. TRADD recruits TRAF2 and RIPK1- dependent apoptosis In contrast to the phenotype of Ripk1–/– mice, mice the E3 ubiquitin ligases cIAP1 and cIAP2 into complex I (RDA). A form of apoptosis enacted by activated RIPK1 harbouring RIPK1 knock- in kinase dead mutations, to mediate RIPK1 K63 ubiquitylation. K63 ubiquityla- kinase that forms a transient including D138N and K45A, or a K584R death domain tion of RIPK1, in turn, mediates the recruitment and intermediate cell death mutation that blocks the dimerization- mediated activation of TAK1 kinase through the polyubiquitin complex comprising highly activation of RIPK1 are normal19,27,28. In fact, these binding adaptors TAB2 and TAB3 (REF.36). K63 ubiq- ubiquitylated, activated RIPK1, FADD and Casp8, known as mutant mice are resistant to various inflammatory uitylation of complex I facilitates the recruitment of iuRIPK1 complex, which then and degenerative conditions in mouse models of dis- the LUBAC complex containing HOIP, HOIL1 and transitions to form complex IIa ease. Interestingly, both genetic and pharmacological SHARPIN, which in turn performs M1 ubiquitylation to mediate the activation of inhibition of RIPK1 kinase activity, such as treatment of RIPK1 and TNFR1. M1 ubiquitylation of complex I is Casp8. with Nec-1s or GNE684 (REFS10,29), offer complete resist- important for the recruitment of the trimeric IKK com- ance against the TNF- induced animal model of septic plex through the polyubiquitin- binding adaptor sub- shock30,31,32. Thus, the kinase activity of RIPK1 pro- unit IKKγ/NEMO2,37, as well as other ubiquitin binding motes cell death and inflammation whereas the scaffold proteins such as ABIN1 (A20 binding and inhibitor of function of RIPK1 supports postnatal survival. NF-κB-1) and the kinase
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