生物活性

• 描述Class I PI3Ks are dual-specific lipid and protein kinases involved in numerous intracellular signaling pathways. Class IA includes three catalytic subunits, p110α (encoded by Pik3ca), p110β (encoded by Pik3cb) and p110δ (encoded by Pik3cd), which are activated through tyrosine kinase signaling. Class IB p110γ is mainly activated by seven-transmembrane G-protein-coupled receptors (GPCRs). Whereas expression of PI3Kα and β is ubiquitous, that of PI3Kγ and δ is mainly restricted to the hematopoietic system. AS-604850 is a selective and ATP-competitive PI3Kγ inhibitor with an IC₅₀ value of 250 nM and a K_i value of 0.18 μM. AS-604850 shows inhibitory activity of PI3Kγ with over 30-fold selectivity for PI3Kδ and β, and 18-fold selectivity over PI3Kα. AS-604850 inhibited C5a-mediated PKB phosphorylation in RAW264 mouse macrophages with an IC₅₀ value of 10 μM. AS-604850 blocked MCP-1–mediated chemotaxis in Pik3cg^+/+ monocytes in a concentration-dependent manner, with an IC₅₀ of 21 μM, but did not affect chemotaxis in Pik3cg^–/– cells, indicating that AS-604850 acts through PI3Kγ. In mouse models of peritonitis induced by RANTES (also known as CCL5), AS-604850 reduced RANTES-induced peritoneal neutrophil recruitment, with a half-maximal efficacious dose (ED₅₀) of 42.4 mg/kg. In the thioglycollate-induced peritonitis model, oral administration of 10 mg/kg AS-604850 resulted in a 31% reduction of neutrophil recruitment^[2].