Discovery of Selective 4-Amino-pyridopyrimidine Inhibitors of MAP4K4 Using Fragment-Based Lead Identification and Optimization
Discovery of Selective 4-Amino-pyridopyrimidine Inhibitors of MAP4K4 Using Fragment-Based Lead Identification and Optimization
复制标题
DOI：
10.1021/jm500155b
复制
发表时间：
2014-04-24
影响因子：
7.3
通讯作者：
Ye, Weilan
中科院分区：
文献类型：
--
作者：
Crawford, Terry D.;Ndubaku, Chudi O.;Ye, Weilan
丝裂原激活蛋白激酶激酶激酶 4 (MAP4K4) 是一种丝氨酸/苏氨酸激酶，参与许多生物过程的调节。基于片段的先导化合物发现方法用于生成有效且选择性的 MAP4K4 抑制剂。本文所追求的片段命中具有出色的配体效率（LE），这是后续成功优化为类药物先导化合物的重要属性。优化工作最终使我们将重点放在吡啶并嘧啶系列上，并从中鉴定出 6-(2-氟吡啶-4-基)吡啶并[3,2-d]嘧啶-4-胺 (29)。该化合物具有低纳摩尔效力、优异的激酶选择性和良好的体内暴露性，并在人类肿瘤异种移植模型中证明了体内药效学作用。
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.