生物活性

• 靶点

  PI3Kα IC50:35nM

  PI3Kβ IC50:4nM

  PI3Kγ IC50:675nM

  PI3Kδ IC50:12nM

• 描述Several studies have highlighted the dependency of PTEN deficiency to PI3Kβ activity. For example, conditional knockout of PIK3CB, the gene coding for the p110β subunit, can block the formation of prostate tumours in mouse models, which shows the important role of PI3Kβ in the occurrence of prostate tumour driven by PTEN loss/mutant^[1]. AZD8186 is a potent and selective inhibitor of PI3Kβ/δ with IC50 of 4 nM and 12 nM (measured by using a Kinase-Glo Plus Assay Kit), respectively, less potent to PI3Kα (IC50=35 nM)^[2]. Treatment of 3 nM of AZD8186 can inhibit 50% level of PI3Kβ-dependent activation of pAKT-Ser473 in PTEN-null, MDA-MB-468, cell line, as well as 17 nM of AZD8186 can inhibit IgM-stimulated pAKT-Ser473, which is activated through PI3Kδ, in JEKO cells. These indicate AZD8186 selectively inhibits PI3Kβ- andδ-mediated signaling through AKT in vitro. In the study of growth inhibition by AZD8186, it was found that AZD8186 is effective in breast and prostate lines, but show more reliable on loss of PTEN in prostate lines. AZD8186 is effective to combination therapy in prostate cancer preclinical models. 10 and 30 mg/kg AZD8186 with 15 mg/kg docetaxel showed regressions in PC3 tumor model^[3].

• 动物研究
  剂量	Mice: 25 mg/kg, 50 mg/kg[3] (s.c.), 60 mg/kg[2] (p.o.)
  给药途径	s.c., p.o.
  动物药代数据	Animal Mice Dogs Dose 30 μmol/kg Administration p.o. p.o. CL 77 mL/min/kg 36 mL/min/kg F 0.18 0.23 AUC 1.2 μM·h Vd 1.3 L/kg 2.2 L/kg