Scaffold-Hopping Approach To Discover Potent, Selective, and Efficacious Inhibitors of NF-κB Inducing Kinase

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.