4ZK5

MAP4K4 in complex with inhibitor GNE-495

4ZK5 の概要

• エントリーDOI: 10.2210/pdb4zk5/pdb
• 分子名称: Mitogen-activated protein kinase kinase kinase kinase 4, MAGNESIUM ION, 2-(N-MORPHOLINO)-ETHANESULFONIC ACID, ... (5 entities in total)
• 機能のキーワード: kinase, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• 由来する生物種: Homo sapiens (Human)
• 細胞内の位置: Cytoplasm : O95819
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 76365.12

構造登録者

Harris, S.F.,Wu, P.,Coons, M. (登録日: 2015-04-29, 公開日: 2015-09-02, 最終更新日: 2024-03-06)

主引用文献

Ndubaku, C.O.,Crawford, T.D.,Chen, H.,Boggs, J.W.,Drobnick, J.,Harris, S.F.,Jesudason, R.,McNamara, E.,Nonomiya, J.,Sambrone, A.,Schmidt, S.,Smyczek, T.,Vitorino, P.,Wang, L.,Wu, P.,Yeung, S.,Chen, J.,Chen, K.,Ding, C.Z.,Wang, T.,Xu, Z.,Gould, S.E.,Murray, L.J.,Ye, W.
Structure-Based Design of GNE-495, a Potent and Selective MAP4K4 Inhibitor with Efficacy in Retinal Angiogenesis.
Acs Med.Chem.Lett., 6:913-918, 2015

PubMed 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.

PubMed: 26288693
DOI: 10.1021/acsmedchemlett.5b00174

実験手法

X-RAY DIFFRACTION (2.89 Å)