GNE-495

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 target¹. 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 potency². 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 mice².

溶解方案(细胞实验)

DMSO 中的溶解度 : 2.17 mg/mL (5.35 mM; 超声助溶; 吸湿的 DMSO 对产品的溶解度有显著影响，请使用新开封的 DMSO)

溶解方案(动物实验)

"方案 一": "请依序添加每种溶剂：10% DMSO 40% PEG300 5% Tween-80 45% SalineSolubility: ≥ 0.22 mg/mL (0.54 mM); 澄清溶液 此方案可获得 ≥ 0.22 mg/mL（饱和度未知）的澄清溶液。以 1 mL 工作液为例，取 100 μL 2.2 mg/mL 的澄清 DMSO 储备液加到 400 μL PEG300 中，混合均匀；再向上述体系中加入 50 μL Tween-80，混合均匀；然后再继续加入 450 μL 生理盐水 定容至 1 mL。生理盐水的配制：将 0.9 g 氯化钠，溶解于 ddH₂O 并定容至 100 mL，可以得到澄清透明的生理盐水溶液。"

"方案 二": "请依序添加每种溶剂：10% DMSO 90% (20% SBE-β-CD in Saline)Solubility: ≥ 0.22 mg/mL (0.54 mM); 澄清溶液 此方案可获得 ≥ 0.22 mg/mL（饱和度未知）的澄清溶液。以 1 mL 工作液为例，取 100 μL 2.2 mg/mL 的澄清 DMSO 储备液加到 900 μL 20% 的 SBE-β-CD 生理盐水水溶液 中，混合均匀。2 g SBE-β-CD（磺丁基醚 β-环糊精）粉末定容于 10 mL 的生理盐水中，完全溶解至澄清透明。"

"方案 三": "请依序添加每种溶剂：10% DMSO 90% Corn OilSolubility: ≥ 0.22 mg/mL (0.54 mM); 澄清溶液 此方案可获得 ≥ 0.22 mg/mL（饱和度未知）的澄清溶液，此方案实验周期在半个月以上的动物实验酌情使用。以 1 mL 工作液为例，取 100 μL 2.2 mg/mL 的澄清 DMSO 储备液加到 900 μL玉米油中，混合均匀。"