6g4y

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^[2]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.