Scaffold-Hopping Approach To Discover Potent, Selective, and Efficacious Inhibitors of NF-κB Inducing Kinase PMID: 29940120

Target-related Cytokines

2026-09-23

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

J Med Chem. 2018 Aug 9;61(15):6801-6813. doi: 10.1021/acs.jmedchem.8b00678.

Nicole Blaquiere ¹ , Georgette M Castanedo ¹ , Jason D Burch ¹ , Leonid M Berezhkovskiy ¹ , Hans Brightbill ¹ , Suzanne Brown ¹ , Connie Chan ¹ , Po-Chang Chiang ¹ , James J Crawford ¹ , Teresa Dong ¹ , Peter Fan ¹ , Jianwen Feng ¹ , Nico Ghilardi ¹ , Robert Godemann ² , Emily Gogol ¹ , Alice Grabbe ² , Alison J Hole ² , Baihua Hu ³ , Sarah G Hymowitz ¹ , Moulay Hicham Alaoui Ismaili ¹ , Hoa Le ¹ , Patrick Lee ¹ , Wyne Lee ¹ , Xingyu Lin ³ , Ning Liu ¹ , Paul A McEwan ² , Brent McKenzie ¹ , Hernani L Silvestre ² , Eric Suto ¹ , Swathi Sujatha-Bhaskar ¹ , Guosheng Wu ³ , Lawren C Wu ¹ , Yamin Zhang ³ , Zoe Zhong ¹ , Steven T Staben ¹

Affiliations

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.