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Discovery of selective 4-Amino-pyridopyrimidine inhibitors of MAP4K4 using fragment-based lead identification and optimization.

Abstract：

:Mitogen-activated protein kinase kinase kinase kinase 4 (MAP4K4) is a serine/threonine kinase implicated in the regulation of many biological processes. A fragment-based lead discovery approach was used to generate potent and selective MAP4K4 inhibitors. The fragment hit pursued in this article had excellent ligand efficiency (LE), an important attribute for subsequent successful optimization into drug-like lead compounds. The optimization efforts eventually led us to focus on the pyridopyrimidine series, from which 6-(2-fluoropyridin-4-yl)pyrido[3,2-d]pyrimidin-4-amine (29) was identified. This compound had low nanomolar potency, excellent kinase selectivity, and good in vivo exposure, and demonstrated in vivo pharmacodynamic effects in a human tumor xenograft model.

journal_name

J Med Chem

journal_title

Journal of medicinal chemistry

authors

Crawford TD,Ndubaku CO,Chen H,Boggs JW,Bravo BJ,Delatorre K,Giannetti AM,Gould SE,Harris SF,Magnuson SR,McNamara E,Murray LJ,Nonomiya J,Sambrone A,Schmidt S,Smyczek T,Stanley M,Vitorino P,Wang L,West K,Wu P,Ye W

doi

10.1021/jm500155b

subject

Has Abstract

pub_date

2014-04-24 00:00:00

pages

3484-93

issue

8

eissn

0022-2623

issn

1520-4804

journal_volume

57

pub_type

杂志文章

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