AZD8055 is a novel ATP-competitivemTORinhibitor withIC50of 0.8 nM with excellent selectivity(?1,000-fold) against PI3K isoforms and ATM/DNA-PK.Phase 1.
生化机理
AZD8055 shows low activity(~1,000-fold) against all PI3K isoforms(α,β,γ,δ) and other members of the PI3K-like kinase family(ATM and DNA-PK).AZD8055 inhibits the phosphorylation of mTORC1(p70S6K and 4E-BP1) as well as phosphorylation of the mTORC2(Akt) and downstream proteins.The rapamycin-resistant T37/46 phosphorylation sites on 4E-BP1 can be fully inhibited by AZD8055,resulting in significant inhibition of cap-dependent translation.AZD8055 potently inhibits proliferation in U87MG,A549 and H838 cells with IC50 of 53,50 and 20 nM,respectively.AZD8055 also induces autophagy and increased LC3-II levels in H838 and A549 cells[1].AZD8055 decreases AML blast cell proliferation and cell cycle progression,reduces the clonogenic growth of leukemic progenitors and induces caspase-dependent apoptosis in leukemic cells but not in normal immature CD34+ cells