GNE-495的基于结构的设计，一种在视网膜血管生成中有效的强效且选择性的MAP4K4抑制剂。
Structure-Based Design of GNE-495, a Potent and Selective MAP4K4 Inhibitor with Efficacy in Retinal Angiogenesis.
作者信息
Ndubaku Chudi O, Crawford Terry D, Chen Huifen, Boggs Jason W, Drobnick Joy, Harris Seth F, Jesudason Rajiv, McNamara Erin, Nonomiya Jim, Sambrone Amy, Schmidt Stephen, Smyczek Tanya, Vitorino Philip, Wang Lan, Wu Ping, Yeung Stacey, Chen Jinhua, Chen Kevin, Ding Charles Z, Wang Tao, Xu Zijin, Gould Stephen E, Murray Lesley J, Ye Weilan
机构信息
Genentech, Inc. , 1 DNA Way, South San Francisco, California 94080, United States.
Wuxi Apptec Co., Ltd. , 288 Fute Zhong Road, Waigaoqiao Free Trade Zone, Shanghai 200131, People's Republic of China.
出版信息
ACS Med Chem Lett. 2015 Jun 29;6(8):913-8. doi: 10.1021/acsmedchemlett.5b00174. eCollection 2015 Aug 13.
Abstract
Diverse biological roles for mitogen-activated protein kinase kinase kinase kinase 4 (MAP4K4) have necessitated the identification of potent inhibitors in order to study its function in various disease contexts. In particular, compounds that can be used to carry out such studies in vivo would be critical for elucidating the potential for therapeutic intervention. A structure-based design effort coupled with property-guided optimization directed at minimizing the ability of the inhibitors to cross into the CNS led to an advanced compound 13 (GNE-495) that showed excellent potency and good PK and was used to demonstrate in vivo efficacy in a retinal angiogenesis model recapitulating effects that were observed in the inducible Map4k4 knockout mice.
摘要
丝裂原活化蛋白激酶激酶激酶激酶4（MAP4K4）具有多种生物学作用，因此需要鉴定有效的抑制剂，以便在各种疾病背景下研究其功能。特别是，可用于体内此类研究的化合物对于阐明治疗干预的潜力至关重要。基于结构的设计努力与性质导向的优化相结合，旨在最小化抑制剂进入中枢神经系统的能力，从而得到了先进的化合物13（GNE-495），该化合物显示出优异的效力和良好的药代动力学性质，并用于在视网膜血管生成模型中证明体内疗效，该模型重现了在诱导型Map4k4基因敲除小鼠中观察到的效果。
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