Inhibiting NF-κB-inducing kinase (NIK): Discovery, structure-based design, synthesis, structure–activity relationship, and co-crystal structures

Li, Kexue; McGee, Lawrence R.; Fisher, Ben; Sudom, Athena; Liu, Jinsong; Rubenstein, Steven M.; Anwer, Mohmed K.; Cushing, Timothy D.; Shin, Youngsook; Ayres, Merrill; Lee, Fei; Eksterowicz, John; Faulder, Paul; Waszkowycz, Bohdan; Plotnikova, Olga; Farrelly, Ellyn; Xiao, Shou‐Hua; Chen, Guoqing; Wang, Zhong Lin

doi:10.1016/j.bmcl.2013.01.012

Cited by 61 publications

(55 citation statements)

References 28 publications

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“…Potential therapeutic approaches include both the simultaneous inhibition of both NF-κB pathways when targeting TWEAK as well as the eventual independent regulation of canonical and non-canonical NF-κB responses by designing differential inhibitors. While these non-canonical NF-κB inhibitors are not yet ready for human use, progress is being made on the design of NIK inhibitors (77). However, there is little functional information on the overall role of NIK and non-canonical NF-κB activation in kidney disease and on the consequences of differential therapeutically manipulation of canonical and non-canonical NF-κB responses.…”

Section: Resultsmentioning

confidence: 99%

TWEAK/Fn14 and Non-Canonical NF-kappaB Signaling in Kidney Disease

et al. 2013

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The incidence of acute kidney injury (AKI) and chronic kidney disease (CKD) is increasing. However, there is no effective therapy for AKI and current approaches only slow down, but do not prevent progression of CKD. TWEAK is a TNF superfamily cytokine. A solid base of preclinical data suggests a role of therapies targeting the TWEAK or its receptor Fn14 in AKI and CKD. In particular TWEAK/Fn14 targeting may preserve renal function and decrease cell death, inflammation, proteinuria, and fibrosis in mouse animal models. Furthermore there is clinical evidence for a role of TWEAK in human kidney injury including increased tissue and/or urinary levels of TWEAK and parenchymal renal cell expression of the receptor Fn14. In this regard, clinical trials of TWEAK targeting are ongoing in lupus nephritis. Nuclear factor-kappa B (NF-κB) activation plays a key role in TWEAK-elicited inflammatory responses. Activation of the non-canonical NF-κB pathway is a critical difference between TWEAK and TNF. TWEAK activation of the non-canonical NF-κB pathways promotes inflammatory responses in tubular cells. However, there is an incomplete understanding of the role of non-canonical NF-κB activation in kidney disease and on its contribution to TWEAK actions in vivo.

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Section: Resultsmentioning

confidence: 99%

TWEAK/Fn14 and Non-Canonical NF-kappaB Signaling in Kidney Disease

et al. 2013

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“…Thus, MAP3K14 represents a key regulated step promoting AKI that may potentially be subject to therapeutic manipulation, although at present there are no satisfactory MAP3K14 inhibitors. 42 MAP3K14 is the essential upstream serine/threonine kinase of the noncanonical NFkB pathway that binds to TRAF2 and participates in NFkB signaling in response to the TNF superfamily and IL-1 receptors. 22 MAP3K14 protein concentrations are low in quiescent cells as a result of rapid degradation.…”

Section: Discussionmentioning

confidence: 99%

Mitogen-Activated Protein Kinase 14 Promotes AKI

Ortíz

Husi

González‐Lafuente

et al. 2016

JASN

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An improved understanding of pathogenic pathways in AKI may identify novel therapeutic approaches. Previously, we conducted unbiased liquid chromatography-tandem mass spectrometry-based protein expression profiling of the renal proteome in mice with acute folate nephropathy. Here, analysis of the dataset identified enrichment of pathways involving NFB in the kidney cortex, and a targeted data mining approach identified components of the noncanonical NFB pathway, including the upstream kinase mitogen-activated protein kinase kinase kinase 14 (MAP3K14), the NFB DNA binding heterodimer RelB/NFB2, and proteins involved in NFB2 p100 ubiquitination and proteasomal processing to p52, as upregulated. Immunohistochemistry localized MAP3K14 expression to tubular cells in acute folate nephropathy and human AKI. , kidney expression levels of NFB2 p100 and p52 increased rapidly after folic acid injection, as did DNA binding of RelB and NFB2, detected in nuclei isolated from the kidneys. Compared with wild-type mice, MAP3K14 activity-deficient aly/aly (MAP3K14) mice had less kidney dysfunction, inflammation, and apoptosis in acute folate nephropathy and less kidney dysfunction and a lower mortality rate in cisplatin-induced AKI. The exchange of bone marrow between wild-type and MAP3K14 mice did not affect the survival rate of either group after folic acid injection. In cultured tubular cells, MAP3K14 small interfering RNA targeting decreased inflammation and cell death. Additionally, cell culture and studies identified the chemokines MCP-1, RANTES, and CXCL10 as MAP3K14 targets in tubular cells. In conclusion, MAP3K14 promotes kidney injury through promotion of inflammation and cell death and is a promising novel therapeutic target.

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“…To target NIK selectively in EC, a multimodular recombinant protein that specifically binds to cytokine-activated endothelium under inflammatory conditions, including arthritis, could be used 38 . This could be done with a local intraarticular treatment (e.g., gene therapy) or by using small molecule inhibitors 39 . This could be done with a local intraarticular treatment (e.g., gene therapy) or by using small molecule inhibitors 39 .…”

Section: Discussionmentioning

confidence: 99%