6g4y

Crystal structure of murine NF-kappaB inducing kinase (NIK) in complex with compound 1a

spinqualitylabelsall models 6g4y, resolution 2.65Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 6g4y is a 2 chain structure with sequence from Lk3 transgenic mice. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: ELZ, SO4 Gene: Map3k14, Nik (LK3 transgenic mice) Activity: Mitogen-activated protein kinase kinase kinase, with EC number 2.7.11.25 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function [M3K14_MOUSE] Lymphotoxin beta-activated kinase which seems to be exclusively involved in the activation of NF-kappa-B and its transcriptional activity. Promotes proteolytic processing of NFKB2/P100, which leads to activation of NF-kappa-B via the non-canonical pathway. Could act in a receptor-selective manner. Publication Abstract from PubMed NF-kappaB-inducing kinase (NIK) is a protein kinase central to the non-canonical NF-kappaB pathway downstream from multiple TNF receptor family members, including BAFF, which have been associated with B cell survival and maturation, dendritic cell activation, secondary lymphoid organ development, and bone metabolism. We report herein the discovery of a lead chemical series of NIK-inhibitors that was identified through a scaffold-hopping strategy using structure-based design. Electronic and steric properties of lead compounds were modified to address glutathione conjugation and amide hydrolysis. These highly potent compounds exhibited selective inhibition of LTbetaR-dependent p52 translocation and transcription of NF-kappaB2 related genes. Compound 4f is shown to have a favorable pharmacokinetic profile across species and to inhibit BAFF-induced B cell survival in vitro and reduce splenic marginal zone B cells in vivo. A scaffold-hopping approach to discover potent, selective and efficacious inhibitors of NF-kappaB inducing kinase.,Blaquiere N, Castanedo G, Burch J, Berezhkovskiy L, Brightbill H, Brown S, Chan C, Chiang PC, Crawford JJ, Dong T, Fan P, Feng J, Ghilardi N, Godemann R, Gogol E, Grabbe A, Hole A, Hu B, Hymowitz SG, Alaoui Ismaili MH, Le H, Lee P, Lee W, Lin X, Liu N, McEwan P, McKenzie B, Silvestre H, Suto E, Sujathabhaskar S, Wu G, Wu LC, Zhang Y, Staben ST J Med Chem. 2018 Jun 25. doi: 10.1021/acs.jmedchem.8b00678. PMID:29940120 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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