6G4Z

Crystal structure of murine NF-kappaB inducing kinase (NIK) in complex with compound 2f

Summary for 6G4Z

• Entry DOI: 10.2210/pdb6g4z/pdb
• Descriptor: Mitogen-activated protein kinase kinase kinase 14, 5-fluoranyl-1-[4-[2-[(3~{R})-1-methyl-3-oxidanyl-2-oxidanylidene-pyrrol-3-yl]ethynyl]pyridin-2-yl]indazole-3-carboxamide (3 entities in total)
• Functional Keywords: protein serine/threonine kinase, nf-kappab, map3k14, transferase
• Biological source: Mus musculus (Mouse)
• Total number of polymer chains: 2
• Total formula weight: 77869.61

Authors

Leonardo-Silvestre, H.,McEwan, P.A.,Hymowitz, S.G. (deposition date: 2018-03-28, release date: 2018-07-04, Last modification date: 2024-01-17)

Primary citation

Blaquiere, N.,Castanedo, G.M.,Burch, J.D.,Berezhkovskiy, L.M.,Brightbill, H.,Brown, S.,Chan, C.,Chiang, P.C.,Crawford, J.J.,Dong, T.,Fan, P.,Feng, J.,Ghilardi, N.,Godemann, R.,Gogol, E.,Grabbe, A.,Hole, A.J.,Hu, B.,Hymowitz, S.G.,Alaoui Ismaili, M.H.,Le, H.,Lee, P.,Lee, W.,Lin, X.,Liu, N.,McEwan, P.A.,McKenzie, B.,Silvestre, H.L.,Suto, E.,Sujatha-Bhaskar, S.,Wu, G.,Wu, L.C.,Zhang, Y.,Zhong, Z.,Staben, S.T.
Scaffold-Hopping Approach To Discover Potent, Selective, and Efficacious Inhibitors of NF-kappa B Inducing Kinase.
J. Med. Chem., 61:6801-6813, 2018

PubMed Abstract: NF-κB-inducing kinase (NIK) is a protein kinase central to the noncanonical NF-κB pathway downstream from multiple TNF receptor family members, including BAFF, which has been associated with B cell survival and maturation, dendritic cell activation, secondary lymphoid organ development, and bone metabolism. We report herein the discovery of lead chemical series of NIK inhibitors that were 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 LTβR-dependent p52 translocation and transcription of NF-κB2 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.

PubMed: 29940120
DOI: 10.1021/acs.jmedchem.8b00678

Experimental method

X-RAY DIFFRACTION (2.84 Å)