Inhibitors Targeting RIPK1/RIPK3: Old and New Drugs

Martens, Sofie; Hofmans, Sam; Declercq, Wim; Augustyns, Koen; Vandenabeele, Peter

doi:10.1016/j.tips.2020.01.002

Cited by 127 publications

(133 citation statements)

References 103 publications

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“…Further studies on additional RIPK1 ubiquitination sites will be needed to fully explore cell death-associated RIPK1 ubiquitination. Given that therapeutic targeting of RIPK1 is being tested in multiple clinical trials [34,47], understanding how ubiquitination and other mechanisms regulate activation of RIPK1 may help identify human diseases that would benefit from RIPK1 inhibition. .…”

Section: Discussionmentioning

confidence: 99%

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Impaired RIPK1 ubiquitination sensitizes mice to TNF toxicity and inflammatory cell death

Kist¹,

Kömüves²,

Goncharov³

et al. 2020

Cell Death Differ

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Receptor-interacting protein 1 (RIP1; RIPK1) is a key regulator of multiple signaling pathways that mediate inflammatory responses and cell death. TNF-TNFR1 triggered signaling complex formation, subsequent NF-κB and MAPK activation and induction of cell death involve RIPK1 ubiquitination at several lysine residues including Lys376 and Lys115. Here we show that mutating the ubiquitination site K376 of RIPK1 (K376R) in mice activates cell death resulting in embryonic lethality. In contrast to Ripk1K376R/K376R mice, Ripk1K115R/K115R mice reached adulthood and showed slightly higher responsiveness to TNF-induced death. Cell death observed in Ripk1K376R/K376R embryos relied on RIPK1 kinase activity as administration of RIPK1 inhibitor GNE684 to pregnant heterozygous mice effectively blocked cell death and prolonged survival. Embryonic lethality of Ripk1K376R/K376R mice was prevented by the loss of TNFR1, or by simultaneous deletion of caspase-8 and RIPK3. Interestingly, elimination of the wild-type allele from adult Ripk1K376R/cko mice was tolerated. However, adult Ripk1K376R/cko mice were exquisitely sensitive to TNF-induced hypothermia and associated lethality. Absence of the K376 ubiquitination site diminished K11-linked, K63-linked, and linear ubiquitination of RIPK1, and promoted the assembly of death-inducing cellular complexes, suggesting that multiple ubiquitin linkages contribute to the stability of the RIPK1 signaling complex that stimulates NF-κB and MAPK activation. In contrast, mutating K115 did not affect RIPK1 ubiquitination or TNF stimulated NF-κB and MAPK signaling. Overall, our data indicate that selective impairment of RIPK1 ubiquitination can lower the threshold for RIPK1 activation by TNF resulting in cell death and embryonic lethality.

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Section: Discussionmentioning

confidence: 99%

“…RIPK1 inhibition is also protective in acute disease models such as the TNF-induced systemic inflammatory response syndrome (SIRS) model [31,33]. All these studies suggest that RIPK1 is an attractive drug target in inflammatory and neurodegenerative diseases [32,34].…”

Section: Introductionmentioning

confidence: 99%

Impaired RIPK1 ubiquitination sensitizes mice to TNF toxicity and inflammatory cell death

Kist¹,

Kömüves²,

Goncharov³

et al. 2020

Cell Death Differ

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“…To date, GlaxoSmithKline (GSK) and Denali have tested their RIP1 inhibitors in clinical settings and reported that GSK2982772 and DNL104 were generally well tolerated in human subjects ( Harris et al, 2017 ; Weisel et al, 2017 ; Grievink et al, 2020 ; Jensen et al, 2020 ; Martens S. et al, 2020 ). Denali’s brain-penetrant RIP1 inhibitor DNL104 did not cause any central nervous system toxicities but 37% percent of subjects receiving multiple doses of DNL104 had post-dose liver toxicity ( Grievink et al, 2020 ).…”

Section: Rip1 Inhibitors For Treatment Of Tnf Mediated Inflammatory Dmentioning

confidence: 99%

“…Denali’s brain-penetrant RIP1 inhibitor DNL104 did not cause any central nervous system toxicities but 37% percent of subjects receiving multiple doses of DNL104 had post-dose liver toxicity ( Grievink et al, 2020 ). Denali has, in the meantime, terminated clinical examination of DNL104 and in collaboration with Sanofi entered another RIP1 inhibitor, DNL747, in clinical trials for Alzheimer’s disease, amylotrophic lateral sclerosis, and multiple sclerosis ( Jensen et al, 2020 ; Martens S. et al, 2020 ). GSK2982772 is a systemic, non-brain penetrant RIP1 inhibitor was well-tolerated with no serious adverse events (AEs) and no suggestion of a safety concern ( Weisel et al, 2017 ).…”

Section: Rip1 Inhibitors For Treatment Of Tnf Mediated Inflammatory Dmentioning

confidence: 99%

“…GSK has also ventured into cancer trials with a different RIP1 inhibitor, GSK3145095 ( Harris et al, 2019 ). However, that particular trial, designed to test the ability of RIP1 inhibitor to provide benefit in pancreatic and other solid tumors, was relatively quickly terminated ( Martens S. et al, 2020 ). This may not come as a complete surprise given that protective role of RIP1 inhibition in pancreatic cancer was never fully validated ( Patel et al, 2020 ).…”

Section: Rip1 Inhibitors For Treatment Of Tnf Mediated Inflammatory Dmentioning

confidence: 99%

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The Balance of TNF Mediated Pathways Regulates Inflammatory Cell Death Signaling in Healthy and Diseased Tissues

Webster¹,

Vucic²

2020

Front. Cell Dev. Biol.

178

125

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Tumor necrosis factor alpha (TNF; TNFα) is a critical regulator of immune responses in healthy organisms and in disease. TNF is involved in the development and proper functioning of the immune system by mediating cell survival and cell death inducing signaling. TNF stimulated signaling pathways are tightly regulated by a series of phosphorylation and ubiquitination events, which enable timely association of TNF receptors-associated intracellular signaling complexes. Disruption of these signaling events can disturb the balance and the composition of signaling complexes, potentially resulting in severe inflammatory diseases.

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Discovery of 5‐(1‐benzyl‐1H‐imidazol‐4‐yl)‐1,2,4‐oxadiazole derivatives as novel RIPK1 inhibitors via structure‐based virtual screening

Yu,

Hu,

Yan

et al. 2024

Drug Development Research

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RIPK1 plays a key role in necroptosis and is associated with various inflammatory diseases. Using structure‐based virtual screening, a novel hit with 5‐(1‐benzyl‐1H‐imidazol‐4‐yl)‐1,2,4‐oxadiazole scaffold was identified as an RIPK1 inhibitor with an IC50 value of 1.3 μM. Further structure–activity relationship study was performed based on similarity research and biological evaluation. The molecular dynamics simulation of compound 2 with RIPK1 indicated that it may act as a type II kinase inhibitor. This study provides a highly efficient way to discover novel scaffold RIPK1 inhibitors for further development.

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Inhibitors Targeting RIPK1/RIPK3: Old and New Drugs

Cited by 127 publications

References 103 publications

Impaired RIPK1 ubiquitination sensitizes mice to TNF toxicity and inflammatory cell death

Impaired RIPK1 ubiquitination sensitizes mice to TNF toxicity and inflammatory cell death

The Balance of TNF Mediated Pathways Regulates Inflammatory Cell Death Signaling in Healthy and Diseased Tissues

Discovery of 5‐(1‐benzyl‐1H‐imidazol‐4‐yl)‐1,2,4‐oxadiazole derivatives as novel RIPK1 inhibitors via structure‐based virtual screening

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