生物活性

• 靶点	PI3Kα IC50:32nM

• 描述The three class-Ia PI3Ks (phosphoinositide 3-kinases; p110α/p110β/p110δ) and the sole class-Ib PI3K (p110γ) couple growth factor receptors and G-protein-coupled receptors to a wide range of downstream pathways, they all use PtdIns(4,5)P₂ to produce PtdIns(3,4,5)P₃. The cellular levels of PtdIns(3,4,5)P₃ are tightly controlled by phosphatases, including PTEN (phosphatase and tensin homologue deleted on chromosome 10) which dephosphorylates PtdIns(3,4,5)P₃ back to PtdIns(4,5) P₂. The importance of this pathway in cancer is highlighted by the fact that defects in both the kinase and phosphatase activities are commonly observed in tumours. A66 is a highly selective and specific p110α inhibitor with IC₅₀ value of 32 nM in the cell-free assay. The effect of the A66 S form was tested on SK-OV-3 tumour tissue in vivo using a single dose of 100 mg/kg of body weight to determine whether a long-lasting effect of the drug could be achieved on target tissues. A66 S caused a profound reduction in the phosphorylation of Akt/PKB and p70 S6 kinase at both 1 and 6 h after dosing. This is consistent with A66 S having a full inhibitory effect on PI3K signalling in the tumours during this time. A66 S was dosed QD at 100 mg/kg of body weight for up to 21 days or BID at 75 mg/kg of body weight for 16 days in tumour efficacy studies. Both dosing strategies induced a significant delay in growth of SK-OV-3 xenografted tumours. At the final day of dosing, the average TGI (tumour growth inhibition) for A66 S form was 45.9% of control (QD; P<0.05) and 29.9% of control (BID; P<0.01)^[3].
• 作用机制The carboxamide amine moiety forms hydrogen bonds with the side-chain carbonyl group of Gln⁸⁵⁹ and possibly the backbone carbonyl group of Ser^854[3].