The serine/threonine kinase MAP4K4 is a member of the Ste20p (sterile 20 protein) family. The role of MAP4K4 in immunity, inflammation, metabolic and cardiovascular disease has been recognized. Increasing evidence suggests that MAP4K4 plays an important role in cancer and MAP4K4 may represent a novel actionable cancer therapeutic target[1]. GNE-495 is a potent and selective MAP4K4 inhibitor with an IC50 of 3.7 nM. It shows the best balance of MAP4K4 inhibition, permeability, microsomal stability, and cellular potency[2]. GNE-495 is administered intraperitoneally to neonatal mouse pups at high doses: 25 and 50 mg/kg. GNE-495 shows good in vivo profile in all species tested, with low clearances, moderate terminal half-lives, and reasonable oral exposure levels (F=37-47%). GNE-495 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[2].
作用机制
The amide linker extending from the naphthyridine scaffold effectively replaces two of the water molecules and engages in a hydrogen-bonding interaction to the hinge Cys108 carbonyl. Overall, the binding pocket was completely occupied by the optimized ligand.
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