Structure-Based Design of GNE-495, a Potent and Selective MAP4K4 Inhibitor with Efficacy in Retinal Angiogenesis

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• 作者：Chudi O. Ndubaku ; Terry D. Crawford ; Huifen Chen ; Jason W. Boggs ; Joy Drobnick ; Seth F. Harris ; Rajiv Jesudason ; Erin McNamara ; Jim Nonomiya ; Amy Sambrone ; Stephen Schmidt ; Tanya Smyczek ; Philip Vitorino ; Lan Wang ; Ping Wu ; Stacey Yeung ; Jinhua Chen ; Kevin Chen ; Charles Z. Ding ; Tao Wang ; Zijin Xu ; Stephen E. Gould ; Lesley J. Murray ; Weilan Ye
• 刊名：ACS Medicinal Chemistry Letters
• 出版年：2015
• 出版时间：August 13, 2015
• 年：2015
• 卷：6
• 期：8
• 页码：913-918
• 全文大小：387K
• ISSN：1948-5875

文摘

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.