Identification of RIPK3 Type II Inhibitors Using High-Throughput Mechanistic Studies in Hit Triage

Hart, Amy C.; Abell, Lynn M.; Guo, Junqing; Mertzman, Michael; Padmanabha, Ramesh; Macor, John E.; Chaudhry, Charu; Lü, Hao; O’Malley, K; Shaw, Patrick J.; Weigelt, Carolyn A.; Pokross, Matthew; Kish, Kevin; Kim, Kyoung S.; Cornelius, Lyndon; Douglas, Andrew; Calambur, Deepa; Zhang, Ping; Carpenter, Brian; Pitts, William J.

doi:10.1021/acsmedchemlett.9b00065

Cited by 27 publications

(33 citation statements)

References 28 publications

(60 reference statements)

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“…These include autophosphorylation sites, which mark its activation towards necroptosis, as well as several phosphosites by accessory kinases, which were proposed to inhibit RIPK1's kinase activity. [205]; 4M69 [105]; 4BTF [30]).…”

Section: Post-translational Modifications Of Ripk1mentioning

confidence: 99%

The regulation of necroptosis by post-translational modifications

et al. 2021

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Necroptosis is a caspase-independent, lytic form of programmed cell death whose errant activation has been widely implicated in many pathologies. The pathway relies on the assembly of the apical protein kinases, RIPK1 and RIPK3, into a high molecular weight cytoplasmic complex, termed the necrosome, downstream of death receptor or pathogen detector ligation. The necrosome serves as a platform for RIPK3-mediated phosphorylation of the terminal effector, the MLKL pseudokinase, which induces its oligomerization, translocation to, and perturbation of, the plasma membrane to cause cell death. Over the past 10 years, knowledge of the post-translational modifications that govern RIPK1, RIPK3 and MLKL conformation, activity, interactions, stability and localization has rapidly expanded. Here, we review current knowledge of the functions of phosphorylation, ubiquitylation, GlcNAcylation, proteolytic cleavage, and disulfide bonding in regulating necroptotic signaling. Post-translational modifications serve a broad array of functions in modulating RIPK1 engagement in, or exclusion from, cell death signaling, whereas the bulk of identified RIPK3 and MLKL modifications promote their necroptotic functions. An enhanced understanding of the modifying enzymes that tune RIPK1, RIPK3, and MLKL necroptotic functions will prove valuable in efforts to therapeutically modulate necroptosis. Facts • Post-translational modifications of the RIPK1 and RIPK3 kinases and MLKL pseudokinase regulate their localization, activity, conformation, oligomerization, and protein interactions • To date, principally activating modifications have been reported for RIPK3 and MLKL How do RIPK3 and MLKL modifications control their protein interactions and prompt cell death?

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Section: Post-translational Modifications Of Ripk1mentioning

confidence: 99%

The regulation of necroptosis by post-translational modifications

et al. 2021

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“…To date, several small-molecule compounds (Li et al, 2014;Fauster et al, 2015;Martens et al, 2017Martens et al, , 2020Park et al, 2018;Pan et al, 2019;Hart et al, 2020) have been developed to inhibit RIPK3 activity, providing an impressive toolbox for the investigation of the role of RIPK3 in diverse tissues. These inhibitors of RIPK3 can be divided into three types: ATP mimetic inhibitors targeting the active ATP-binding site in the kinases located between two catalytic domain lobes (type I), targeting the inactive states (type II), and unclassified inhibitors (Muller et al, 2015;Martens et al, 2020; Table 1).…”

Section: Implications For Anti-fibrotic Therapymentioning

confidence: 99%

RIPK3: A New Player in Renal Fibrosis

Shi

Chen

Huang

et al. 2020

Front. Cell Dev. Biol.

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Chronic kidney disease (CKD) is the end result of a plethora of renal insults, including repeated episodes of acute or toxic kidney injury, glomerular, or diabetic kidney disease. It affects a large number of the population worldwide, resulting in significant personal morbidity and mortality and economic cost to the community. Hence it is appropriate to focus on treatment strategies that interrupt the development of kidney fibrosis, the end result of all forms of CKD, in addition to upstream factors that may be specific to certain diseases. However, the current clinical approach to prevent or manage renal fibrosis remains unsatisfactory. The rising importance of receptor-interacting serine/threonineprotein kinase (RIPK) 3 in the inflammatory response and TGF-β1 signaling is increasingly recognized. We discuss here the biological functions of RIPK3 and its role in the development of renal fibrosis.

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“…Four different Ripk3 inhibitors (GSK872, GSK840, GSK843, and RIPK3-IN-1) [ 43 , 44 ] were purchased from MedChemExpress, USA. The concentrations of these inhibitors used were listed in Table 1 .…”

Section: Methodsmentioning

confidence: 99%

Loss of Ripk3 attenuated neutrophil accumulation in a lipopolysaccharide-induced zebrafish inflammatory model

Wen

Chen

et al. 2022

Cell Death Discov.

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Neutrophils are important effector cells during inflammation, which play complex roles. Therefore, investigating the regulation of neutrophil accumulation during inflammation might provide targets for treating related diseases. In the present study, we generated a ripk3-deficient zebrafish line to study the roles of Ripk3 in neutrophil-related inflammation. The homeostatic hematopoiesis and cytokine expression of the ripk3-deficient larvae were unaltered. The ripk3-deficient larvae with caudal fin fold injury exhibited similar neutrophil enrichment with wild-type larvae, suggesting that Ripk3 is not essential for non-infectious inflammatory responses. When challenged with lipopolysaccharide (LPS), the ripk3-deficient larvae showed significantly less neutrophil accumulation in the injection site and differential expression of several key cytokines. Ripk3 inhibitors could also attenuate neutrophil accumulation in wild-type larvae, indicating that Ripk3 could serve as a candidate target for inflammation treatment. In summary, our study indicated that Ripk3 has an essential role in LPS-induced inflammatory responses. It was suggested that the ripk3-deficient zebrafish might be applied in developing infectious disease models, while Ripk3 also has potential as an inflammation-treatment target.

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Identification of RIPK3 Type II Inhibitors Using High-Throughput Mechanistic Studies in Hit Triage

Cited by 27 publications

References 28 publications

The regulation of necroptosis by post-translational modifications

The regulation of necroptosis by post-translational modifications

RIPK3: A New Player in Renal Fibrosis

Loss of Ripk3 attenuated neutrophil accumulation in a lipopolysaccharide-induced zebrafish inflammatory model

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