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2 results on '"Alice Grabbe"'

1. Filling a Nick in NIK: Extending the Half-Life of a NIK Inhibitor Through Structure-Based Drug Design

Author

James J. Crawford, Jianwen Feng, Hans D. Brightbill, Adam R. Johnson, Matthew Wright, Aleksandr Kolesnikov, Wendy Lee, Georgette M. Castanedo, Steven Do, Nicole Blaquiere, Steven T. Staben, Po-Chang Chiang, Peter W. Fan, Matt Baumgardner, Susan Wong, Robert Godemann, Alice Grabbe, Catharina Wiegel, Swathi Sujatha-Bhaskar, Sarah G. Hymowitz, Nicholas Liau, Peter L. Hsu, Paul A. McEwan, Moulay Hicham Alaoui Ismaili, and Matthew L. Landry

Subjects
Organic Chemistry, Clinical Biochemistry, Drug Discovery, Pharmaceutical Science, Molecular Medicine, Molecular Biology, Biochemistry
Published
2023

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

Author

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

Subjects
Models, Molecular, 0301 basic medicine, Cell Survival, Protein Conformation, Protein Serine-Threonine Kinases, Mice, 03 medical and health sciences, 0302 clinical medicine, In vivo, Cell Line, Tumor, Drug Discovery, medicine, Animals, Humans, B-cell activating factor, Protein Kinase Inhibitors, B cell, Dose-Response Relationship, Drug, Chemistry, Kinase, Drug discovery, Dendritic cell, In vitro, Cell biology, 030104 developmental biology, medicine.anatomical_structure, Cell culture, 030220 oncology & carcinogenesis, Molecular Medicine
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.

Published
2018

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