4ZK5

MAP4K4 in complex with inhibitor GNE-495

Summary for 4ZK5

• Entry DOI: 10.2210/pdb4zk5/pdb
• Descriptor: Mitogen-activated protein kinase kinase kinase kinase 4, MAGNESIUM ION, 2-(N-MORPHOLINO)-ETHANESULFONIC ACID, ... (5 entities in total)
• Functional Keywords: kinase, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Homo sapiens (Human)
• Cellular location: Cytoplasm : O95819
• Total number of polymer chains: 2
• Total formula weight: 76365.12

Authors

Harris, S.F.,Wu, P.,Coons, M. (deposition date: 2015-04-29, release date: 2015-09-02, Last modification date: 2024-03-06)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (2.89 Å)