학술논문
Discovery of Selective 4-Amino-pyridopyrimidineInhibitors of MAP4K4 Using Fragment-Based Lead Identification andOptimization.
Document Type
Article
Author
Crawford, Terry D.; Ndubaku, Chudi O.; Chen, Huifen; Boggs, Jason W.; Bravo, Brandon J.; De La Torre, Kelly; Giannetti, Anthony M.; Gould, Stephen E.; Harris, Seth F.; Magnuson, Steven R.; McNamara, Erin; Murray, Lesley J.; Nonomiya, Jim; Sambrone, Amy; Schmidt, Stephen; Smyczek, Tanya; Stanley, Mark; Vitorino, Philip; Wang, Lan; West, Kristina
Source
Subject
*PYRIMIDINES
*DRUG development
*MITOGEN-activated protein kinase kinase
*SERINE/THREONINE kinases
*KINASE inhibitors
*PHARMACODYNAMICS
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Language
ISSN
0022-2623
Abstract
Mitogen-activated protein kinasekinase kinase kinase 4 (MAP4K4)is a serine/threonine kinase implicated in the regulation of manybiological processes. A fragment-based lead discovery approach wasused to generate potent and selective MAP4K4 inhibitors. The fragmenthit pursued in this article had excellent ligand efficiency (LE),an important attribute for subsequent successful optimization intodrug-like lead compounds. The optimization efforts eventually ledus to focus on the pyridopyrimidine series, from which 6-(2-fluoropyridin-4-yl)pyrido[3,2-d]pyrimidin-4-amine (29) was identified. Thiscompound had low nanomolar potency, excellent kinase selectivity,and good in vivo exposure, and demonstrated in vivo pharmacodynamiceffects in a human tumor xenograft model. [ABSTRACT FROM AUTHOR]