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

被引：39

作者：

Blaquiere, Nicole ^{[1
]}

Castanedo, Georgette M. ^{[1
]}

Burch, Jason D. ^{[1
]}

Berezhkovskiy, Leonid M. ^{[1
]}

Brightbill, Hans ^{[1
]}

Brown, Suzanne ^{[1
]}

Chan, Connie ^{[1
]}

Chiang, Po-Chang ^{[1
]}

Crawford, James J. ^{[1
]}

Dong, Teresa ^{[1
]}

Fan, Peter ^{[1
]}

Feng, Jianwen ^{[1
]}

Ghilardi, Nico ^{[1
]}

Godemann, Robert ^{[3
]}

Gogol, Emily ^{[1
]}

Grabbe, Alice ^{[3
]}

Hole, Alison J. ^{[3
]}

Hu, Baihua ^{[2
]}

Hymowitz, Sarah G. ^{[1
]}

Ismaili, Moulay Hicham Alaoui ^{[1
]}

Le, Hoa ^{[1
]}

Lee, Patrick ^{[1
]}

Lee, Wyne ^{[1
]}

Lin, Xingyu ^{[2
]}

Liu, Ning ^{[1
]}

McEwan, Paul A. ^{[3
]}

McKenzie, Brent ^{[1
]}

Silvestre, Hernani L. ^{[3
]}

Suto, Eric ^{[1
]}

Sujatha-Bhaskar, Swathi ^{[1
]}

Wu, Guosheng ^{[2
]}

Wu, Lawren C. ^{[1
]}

Zhang, Yamin ^{[2
]}

Zhong, Zoe ^{[1
]}

Staben, Steven T. ^{[1
]}

机构：

[1] Genentech Inc, 1 DNA Way, San Francisco, CA 94080 USA

[2] Pharmaron Beijing Co Ltd, 6 Taihe Rd, Beijing 100176, Peoples R China

[3] Evotec AG, Manfred Eigen Campus, D-22419 Hamburg, Germany

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2018年 / 61卷 / 15期

关键词：

LYMPHOCYTE STIMULATOR; SIGNALING PATHWAY; PROTEIN-KINASES; ACTIVATION; NIK; IDENTIFICATION; CONFORMATION; DISEASE; TRAF2; ALPHA;

D O I：

10.1021/acs.jmedchem.8b00678

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

NF-kappa B -inducing kinase (NIK) is a protein kinase central to the noncanonical NF-kappa B 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 LT beta R-dependent p52. translocation and transcription of NF-kappa B2 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.

引用

页码：6801 / 6813

页数：13

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