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 met...

Full description

Saved in:
Bibliographic Details
Published in:Journal of medicinal chemistry 2018-08, Vol.61 (15), p.6801-6813
Main Authors: Blaquiere, Nicole, Castanedo, Georgette M, Burch, Jason D, Berezhkovskiy, Leonid M, Brightbill, Hans, Brown, Suzanne, Chan, Connie, Chiang, Po-Chang, Crawford, James J, Dong, Teresa, Fan, Peter, Feng, Jianwen, Ghilardi, Nico, Godemann, Robert, Gogol, Emily, Grabbe, Alice, Hole, Alison J, Hu, Baihua, Hymowitz, Sarah G, Alaoui Ismaili, Moulay Hicham, Le, Hoa, Lee, Patrick, Lee, Wyne, Lin, Xingyu, Liu, Ning, McEwan, Paul A, McKenzie, Brent, Silvestre, Hernani L, Suto, Eric, Sujatha-Bhaskar, Swathi, Wu, Guosheng, Wu, Lawren C, Zhang, Yamin, Zhong, Zoe, Staben, Steven T
Format: Article
Language:English
Subjects:
Animals
Cell Line, Tumor
Cell Survival - drug effects
Dose-Response Relationship, Drug
Drug Discovery
Humans
Mice
Models, Molecular
NF-kappaB-Inducing Kinase
Protein Conformation
Protein Kinase Inhibitors - chemistry
Protein Kinase Inhibitors - pharmacology
Protein Serine-Threonine Kinases - antagonists & inhibitors
Protein Serine-Threonine Kinases - chemistry
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary: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.
ISSN:0022-2623
1520-4804
DOI:10.1021/acs.jmedchem.8b00678