The multitargeted kinase inhibitor KW-2449 ameliorates cisplatin-induced nephrotoxicity by targeting RIPK1-mediated necroptosis

Rui, Chunhua; Shi, Shen-Nan; Ren, Wenqing; Qin, Xia; Zhuang, Chunlin; Chen, Xiaofei; Chen, Gang; Wang, Hongyang; Cai, Zhenyu

doi:10.1016/j.bcp.2021.114542

Cited by 16 publications

(13 citation statements)

References 42 publications

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“…Experimental evidence shows that cisplatin induces necroptosis with tumor necrosis factor α (TNFα)-dependent and independent pathways ( Xu et al, 2017 ). Moreover, multitargeted kinase inhibitor KW-2449 alleviates cisplatin-induced nephrotoxicity through targeting RIPK1-independent necroptosis ( Rui et al, 2021 ). Combination therapy of CD95L and gemcitabine facilitates RIP1-independent necroptosis in pancreatic cancer cells ( Pietkiewicz et al, 2015 ).…”

Section: Discussionmentioning

confidence: 99%

Comprehensive Analysis of Necroptosis in Pancreatic Cancer for Appealing its Implications in Prognosis, Immunotherapy, and Chemotherapy Responses

et al. 2022

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Objective: Necroptosis represents a new target for cancer immunotherapy and is considered a form of cell death that overcomes apoptosis resistance and enhances tumor immunogenicity. Herein, we aimed to determine necroptosis subtypes and investigate the roles of necroptosis in pancreatic cancer therapy.Methods: Based on the expression of prognostic necroptosis genes in pancreatic cancer samples from TCGA and ICGC cohorts, a consensus clustering approach was implemented for robustly identifying necroptosis subtypes. Immunogenic features were evaluated according to immune cell infiltrations, immune checkpoints, HLA molecules, and cancer–immunity cycle. The sensitivity to chemotherapy agents was estimated using the pRRophetic package. A necroptosis-relevant risk model was developed with a multivariate Cox regression analysis.Results: Five necroptosis subtypes were determined for pancreatic cancer (C1∼C5) with diverse prognosis, immunogenic features, and chemosensitivity. In particular, C4 and C5 presented favorable prognosis and weakened immunogenicity; C2 had high immunogenicity; C1 had undesirable prognosis and high genetic mutations. C5 was the most sensitive to known chemotherapy agents (cisplatin, gemcitabine, docetaxel, and paclitaxel), while C4 displayed resistance to aforementioned agents. The necroptosis-relevant risk model could accurately predict prognosis, immunogenicity, and chemosensitivity.Conclusion: Our findings provided a conceptual framework for comprehending necroptosis in pancreatic cancer biology. Future work is required for evaluating its relevance in the design of combined therapeutic regimens and guiding the best choice for immuno- and chemotherapy.

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Section: Discussionmentioning

confidence: 99%

Comprehensive Analysis of Necroptosis in Pancreatic Cancer for Appealing its Implications in Prognosis, Immunotherapy, and Chemotherapy Responses

et al. 2022

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“…Moreover, the multitargeted kinase (FLT3, ABL, ABL-T315I, and Aurora) inhibitor KW-2449 (10, Figure 4B) can be used as a necroptosis inhibitor because it directly inhibits the kinase activity of RIP1. 112 Molecular docking of the KW-2449−RIP1 complex revealed a structure very similar to that of the GNF-7−RIP1 complex. In a mouse model, oral administration of KW-2449 reduced renal cell necrosis and the proinflammatory response caused by cisplatin.…”

Section: Rip1 Inhibitorsmentioning

confidence: 91%

“…In addition, GNF-7 may be a potential lead for developing additional effective compounds for the treatment of acute nephritis. Moreover, the multitargeted kinase (FLT3, ABL, ABL-T315I, and Aurora) inhibitor KW-2449 ( 10 , Figure B) can be used as a necroptosis inhibitor because it directly inhibits the kinase activity of RIP1 . Molecular docking of the KW-2449–RIP1 complex revealed a structure very similar to that of the GNF-7–RIP1 complex.…”

Section: Rip1 Inhibitorsmentioning

confidence: 99%

Small-Molecule Receptor-Interacting Protein 1 (RIP1) Inhibitors as Therapeutic Agents for Multifaceted Diseases: Current Medicinal Chemistry Insights and Emerging Opportunities

et al. 2022

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As a serine/threonine protein kinase, receptor-interacting protein 1 (RIP1) plays an important role in regulating the pathways in programmed cell death. Multifaceted human diseases (e.g., autoimmune diseases, inflammatory diseases, neurodegenerative diseases, and tumors) are closely related to RIP1 kinase. Therefore, small-molecule RIP1 inhibitors with precise targeting and good penetrability have recently been used in potentially therapeutic methods, attracting extensive researcher interest. GSK2982772, developed by GlaxoSmithKline (GSK), became the world’s first RIP1 inhibitor approved for clinical research in 2014. Nine clinical trials assessing GSK2982772 have been performed. The most recent direction in RIP1 inhibitor development has been focused on RIP1 small-molecule inhibitors with higher potency, selectivity, and metabolic stability. In this Perspective, considering the structure, biological functions, and disease relevance of RIP1, we summarize the recent research progress in RIP1 small-molecule inhibitor development based on different binding modalities and discuss prospective strategies for designing additional RIP1 therapeutic agents.

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“…Therefore, rat renal tubular epithelial cells were selected to explore the toxic mechanism of 1,3-DCP in vitro . Different mechanisms lead to nephrotoxicity, including necroptosis, mitochondrial apoptosis, pyroptosis, secretion of inflammatory cytokines, autophagic cell death, oxidative stress, etc. − …”

Section: Introductionmentioning

confidence: 99%

1,3-Dichloro-2-propanol-Induced Renal Tubular Cell Necroptosis through the ROS/RIPK3/MLKL Pathway

Fan

Lü

et al. 2022

J. Agric. Food Chem.

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1,3-Dichloro-2-propanol (1,3-DCP), as a food pollutant, exists in a variety of foods. Studies have shown that it has nephrotoxicity. In the study, we found that 1,3-DCP caused renal injury with necroptosis in C57BL/6J mice. The mechanism of 1,3-DCP-caused nephrotoxicity was further explored in NRK-52E cells in vitro. We found that 1,3-DCP caused cell necroptosis with the increase in lactate dehydrogenase (LDH) levels and the expressions of RIPK3 and MLKL. But pretreatment with a ROS inhibitor Nacetyl-L-cysteine (NAC), a RIPK3 inhibitor GSK'872, or RIPK3 gene silencing alleviated 1,3-DCP-induced cell necroptosis. The data indicated that 1,3-DCP induced necroptosis through the ROS/RIPK3/MLKL pathway in NRK-52E cells. In further mechanistic studies, we explored how 1,3-DCP induced ROS production. We found that 1,3-DCP inhibited the expressions of nuclear and cytoplasmic Nrf2. But pretreatment with an Nrf2 activator dimethyl fumarate (DMF) up-regulated the expressions of nuclear and cytoplasmic Nrf2 and down-regulated ROS levels and RIPK3 and MLKL expressions. We also examined the effects of mitophagy on 1,3-DCP-induced ROS. The data manifested that 1,3-DCP suppressed mitophagy in NRK-52E cells by decreasing LC3-II, Pink1, and Parkin levels, increasing p62 levels, and decreasing colocalization of LC3 and Mito-Tracker Red. Pretreatment with an autophagy activator rapamycin (Rapa) decreased 1,3-DCP-induced ROS. Taken together, our data identified that 1,3-DCP caused renal necroptosis through the ROS/RIPK3/MLKL pathway.

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The multitargeted kinase inhibitor KW-2449 ameliorates cisplatin-induced nephrotoxicity by targeting RIPK1-mediated necroptosis

Cited by 16 publications

References 42 publications

Comprehensive Analysis of Necroptosis in Pancreatic Cancer for Appealing its Implications in Prognosis, Immunotherapy, and Chemotherapy Responses

Comprehensive Analysis of Necroptosis in Pancreatic Cancer for Appealing its Implications in Prognosis, Immunotherapy, and Chemotherapy Responses

Small-Molecule Receptor-Interacting Protein 1 (RIP1) Inhibitors as Therapeutic Agents for Multifaceted Diseases: Current Medicinal Chemistry Insights and Emerging Opportunities

1,3-Dichloro-2-propanol-Induced Renal Tubular Cell Necroptosis through the ROS/RIPK3/MLKL Pathway

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