4zk5
From Proteopedia
MAP4K4 in complex with inhibitor GNE-495
Structural highlights
FunctionM4K4_HUMAN Serine/threonine kinase that may play a role in the response to environmental stress and cytokines such as TNF-alpha. Appears to act upstream of the JUN N-terminal pathway. Phosphorylates SMAD1 on Thr-322.[1] [2] Publication Abstract from PubMedDiverse 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. Structure-Based Design of GNE-495, a Potent and Selective MAP4K4 Inhibitor with Efficacy in Retinal Angiogenesis.,Ndubaku CO, Crawford TD, Chen H, Boggs JW, Drobnick J, Harris SF, 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 CZ, Wang T, Xu Z, Gould SE, Murray LJ, Ye W ACS Med Chem Lett. 2015 Jun 29;6(8):913-8. doi: 10.1021/acsmedchemlett.5b00174., eCollection 2015 Aug 13. PMID:26288693[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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