MSC2363318A, also known as M2698, is an orally available inhibitor of the serine/threonine protein kinases ribosomal protein S6 Kinase (p70S6K) andAkt (protein kinase B), with potential antineoplastic activity.
M2698, an oral, ATP-competitive inhibitor, selectively targets p70S6K and Akt with IC50s of 1 nM for both p70S6K and Akt1/3. It is capable of crossing the blood-brain barrier and exhibits anti-cancer properties. At concentrations ranging from 0.3 nM to 50 M over 72 hours, M2698 dose-dependently curbs the proliferation of breast tumor cell lines, with IC50s between 0.02-8.5 µM. Additionally, at 0.3 and 1 µM for 24 hours, it inhibits p70S6K activity, triggers feedback phosphorylation on Akt, and reduces Akt activity in these cell lines. M2698 indirectly inhibits pGSK3β (IC50=17 nM) and pS6 (IC50=15 nM)[1].
M2698 动物研究
Animal study
When administered orally at doses of 10-30 mg/kg/day for 28 days, M2698 achieves dose-dependent tumor growth inhibition and causes tumor regression at the maximum dose of 30 mg/kg. When administered at 20 mg/kg/day orally for 4 days, M2698 exhibits a tumor to plasma exposure ratio of 12:1 over a 24-hour period and results in elevated pAkt levels in tumor tissues. The average total concentration of M2698 following a 16-hour infusion in rats is 1750 ng/g in the brain and 175 ng/mL in plasma. Furthermore, M2698, given orally in doses of 1, 5, 10, or 20 mg/kg/day for 7 days, proportionally inhibits the phosphorylation of S6 over time, whether after a single dose or continuous daily treatments over the course of 7 days[1].
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