Receptor-interacting protein kinase 1 (RIPK1) as a therapeutic target

Mifflin, Lauren; Ofengeim, Dimitry; Yuan, Junying

doi:10.1038/s41573-020-0071-y

Cited by 282 publications

(325 citation statements)

References 219 publications

(328 reference statements)

Supporting

Mentioning

301

Contrasting

Order By: Relevance

“…[47] and our own data). Accordingly, some RIPK1 kinase inhibitors are now in phase I clinical trials for ALS and phase II clinical trials for psoriasis, rheumatoid arthritis, and ulcerative colitis [48], but to date no pharmacological inhibitor of RIPK1-mediated cell death is approved for regular clinical use. The latter was the impetus for our study, namely, evaluating FDA-approved drugs independently of their current clinical applications and assessing their utility in terms of regulated cell death inhibition.…”

Section: Discussionmentioning

confidence: 99%

Primidone blocks RIPK1-driven cell death and inflammation

et al. 2020

View full text Add to dashboard Cite

The receptor-interacting serine/threonine protein kinase 1 (RIPK1) is a key mediator of regulated cell death and inflammation. Recent studies suggest that RIPK1 inhibition would fundamentally improve the therapy of RIPK1-dependent organ damage in stroke, myocardial infarction, kidney failure, and systemic inflammatory response syndrome. Additionally, it could ameliorate or prevent multi-organ failure induced by cytokine release in the context of hyperinflammation, as seen in COVID-19 patients. Therefore, we searched for a RIPK1 inhibitor and present the aromatic antiepileptic and FDA-approved drug primidone (Liskantin®) as a potent inhibitor of RIPK1 activation in vitro and in a murine model of TNFα-induced shock, which mimics the hyperinflammatory state of cytokine release syndrome. Furthermore, we detected for the first time RIPK1 activation in the respiratory tract epithelium of hospitalized patients who tested positive for SARS-CoV-2 infection. Our data provide a strong rationale for evaluating the drug primidone in conditions of hyperinflammation in humans.

show abstract

Section: Discussionmentioning

confidence: 99%

Primidone blocks RIPK1-driven cell death and inflammation

et al. 2020

View full text Add to dashboard Cite

show abstract

“…Necroptosis is a form of regulated cell death that shows necrotic features including cell swelling and disrupted cell membrane. Necroptosis is tightly regulated by the activation of receptor-interacting protein kinase 1 (RIPK1 or RIP1) and RIPK3 (RIP3; Linkermann and Green, 2014 ; He and Wang, 2018 ; Mifflin et al, 2020 ). In TNF-induced necroptosis, RIPK1 interacts with RIPK3 through their RIP homotypic interaction motif (RHIM) domains, leading to RIPK3 activation and phosphorylation ( Holler et al, 2000 ; Cho et al, 2009 ; He et al, 2009 ; Zhang et al, 2009 ).…”

Section: Introductionmentioning

confidence: 99%

Discovery of a Potent RIPK3 Inhibitor for the Amelioration of Necroptosis-Associated Inflammatory Injury

Xia

Zhu

Yang

et al. 2020

Front. Cell Dev. Biol.

View full text Add to dashboard Cite

Necroptosis is a form of regulated necrosis that requires the activation of receptor-interacting kinase 3 (RIPK3 or RIP3) and its phosphorylation of the substrate MLKL (mixed lineage kinase domain-like protein). Necroptosis has emerged as important cell death involved in the pathogenesis of various diseases including inflammatory diseases, degenerative diseases, and cancer. Here, we discovered a small molecule Zharp-99 as a potent inhibitor of necroptosis through blocking the kinase activity of RIPK3. Zharp-99 efficiently blocks necroptosis induced by ligands of the death receptor and Toll-like receptor as well as viral infection in human, rat and mouse cells. Zharp-99 strongly inhibits cellular activation of RIPK3, and MLKL upon necroptosis stimuli. Zharp-99 directly blocks the kinase activity of RIPK3 without affecting RIPK1 kinase activity at the tested concentration. Importantly, Zharp-99 exerts effective protection against TNF-α induced systemic inflammatory response syndrome in the mouse model. Zharp-99 displays favorable in vitro safety profiles and in vivo pharmacokinetic parameters. Thus, our study demonstrates Zharp-99 as a potent inhibitor of RIPK3 kinase and also highlights its potential for further development of new approaches for treating necroptosis-associated inflammatory disorders.

show abstract

“…RIPK1 contains a N-terminal kinase domain, a C-terminal death-domain (DD) and an intermediate domain that contains a RIP homotypic interaction motif (RHIM). In TNFα-stimulated cells, RIPK1 kinase performs pro-cell-death and pro-inflammatory activities by activating RIPK1-dependent apoptosis and necroptosis 1 , 2 . However, the scaffold of RIPK1 is also known to perform pro-survival function independent of its kinase activity.…”

Section: Introductionmentioning

confidence: 99%

Ubiquitination of RIPK1 regulates its activation mediated by TNFR1 and TLRs signaling in distinct manners

Zhang

Huang

et al. 2020

Nat Commun

Self Cite

View full text Add to dashboard Cite

RIPK1 is a death-domain (DD) containing kinase involved in regulating apoptosis, necroptosis and inflammation. RIPK1 activation is known to be regulated by its DD-mediated interaction and ubiquitination, though underlying mechanisms remain incompletely understood. Here we show that K627 in human RIPK1-DD and its equivalent K612 in murine RIPK1-DD is a key ubiquitination site that regulates the overall ubiquitination pattern of RIPK1 and its DD-mediated interactions with other DD-containing proteins. K627R/K612R mutation inhibits the activation of RIPK1 and blocks both apoptosis and necroptosis mediated by TNFR1 signaling. However, Ripk1K612R/K612R mutation sensitizes cells to necroptosis and caspase-1 activation in response to TLRs signaling. Ripk1K612R/K612R mice are viable, but develop age-dependent reduction of RIPK1 expression, spontaneous intestinal inflammation and splenomegaly, which can be rescued by antibiotic treatment and partially by Ripk3 deficiency. Furthermore, we show that the interaction of RIPK1 with FADD contributes to suppressing the activation of RIPK3 mediated by TLRs signaling. Our study demonstrates the distinct roles of K612 ubiquitination in mRIPK1/K627 ubiquitination in hRIPK1 in regulating its pro-death kinase activity in response to TNFα and pro-survival activity in response to TLRs signaling.

show abstract

Receptor-interacting protein kinase 1 (RIPK1) as a therapeutic target

Cited by 282 publications

References 219 publications

Primidone blocks RIPK1-driven cell death and inflammation

Primidone blocks RIPK1-driven cell death and inflammation

Discovery of a Potent RIPK3 Inhibitor for the Amelioration of Necroptosis-Associated Inflammatory Injury

Ubiquitination of RIPK1 regulates its activation mediated by TNFR1 and TLRs signaling in distinct manners

Contact Info

Product

Resources

About