1449277-10-4Relevant articles and documents
MAP4K4 regulates integrin-FERM binding to control endothelial cell motility
Vitorino, Philip,Yeung, Stacey,Crow, Ailey,Bakke, Jesse,Smyczek, Tanya,West, Kristina,McNamara, Erin,Eastham-Anderson, Jeffrey,Gould, Stephen,Harris, Seth F.,Ndubaku, Chudi,Ye, Weilan
, p. 425 - 430 (2015/04/14)
Cell migration is a stepwise process that coordinates multiple molecular machineries. Using in vitro angiogenesis screens with short interfering RNA and chemical inhibitors, we define here a MAP4K4-moesin-talin-? 21-integrin molecular pathway that promotes efficient plasma membrane retraction during endothelial cell migration. Loss of MAP4K4 decreased membrane dynamics, slowed endothelial cell migration, and impaired angiogenesis in vitro and in vivo. In migrating endothelial cells, MAP4K4 phosphorylates moesin in retracting membranes at sites of focal adhesion disassembly. Epistasis analyses indicated that moesin functions downstream of MAP4K4 to inactivate integrin by competing with talin for binding to ? 21-integrin intracellular domain. Consequently, loss of moesin (encoded by the MSN gene) or MAP4K4 reduced adhesion disassembly rate in endothelial cells. Additionally, ?± 5? 21-integrin blockade reversed the membrane retraction defects associated with loss of Map4k4 in vitro and in vivo. Our study uncovers a novel aspect of endothelial cell migration. Finally, loss of MAP4K4 function suppressed pathological angiogenesis in disease models, identifying MAP4K4 as a potential therapeutic target.
Structure-Based Design of GNE-495, a Potent and Selective MAP4K4 Inhibitor with Efficacy in Retinal Angiogenesis
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
, p. 913 - 918 (2015/08/24)
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.
ISOQUINOLINE AND NAPHTHYRIDINE DERIVATIVES
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, (2013/08/15)
The invention provides novel compounds having the general formula(I) wherein A, R1 and R2 are as described herein, compositions including the compounds and use of the compounds for inhibiting angiogenesis by inhibition of MAP4K4.
