AS-604850

AS-604850 is a potent, selective and ATP-competitive PI3Kγ inhibitor with an IC50 value of 0.25 μM and a Ki value of 0.18 μM. AS-604850 shows isoform selective inhibitor of PI3Kγ with over 30-fold selectivity for PI3Kδ and β, and 18-fold selectivity over PI3Kα, respectively[1].

AS-604850 inhibits C5a-mediated PKB phosphorylation with an IC50 of 10 μM in RAW264 mouse macrophages[1].AS-604850 blocks PKB phosphorylation induced by MCP-1 and has little or no effect after stimulation with CSF-1 in in primary monocytes from Pik3cg+/+ or Pik3cg-/- mice[1].AS-604850 (0-30 μM; 15 minutes; primary monocytes from Pik3cg+/+ mice) treatment inhibits MCP-1-mediated phosphorylation of PKB and its downstream substrates GSK3α andβ in a concentration-dependent manner. MCP-1-induced phosphorylation of p44/42 ERK (ERK1/2) MAPKs is also reduced, in a concentration dependent manner in primary monocytes from Pik3cg+/+ mice[1]. Western Blot Analysis[1] Cell Line: Primary monocytes from Pik3cg+/+ mice

AS-604850 (10-100 mg/kg; oral administration; for 4.5 or 4.25 hours; Balb/C or C3H mice) treatment reduces RANTES-induced peritoneal neutrophil recruitment with an ED50 value of 42.4 mg/kg. In the thioglycollate-induced peritonitis model, oral administration of 10 mg/kg AS-604850 results in a 31% reduction of neutrophil recruitment[1]. Animal Model: Balb/C or C3H mice with human recombinant RANTES or thioglycollate[1]

[1]. Camps M, et al. Blockade of PI3Kgamma suppresses joint inflammation and damage in mouse models of rheumatoid arthritis. Nat Med. 2005 Sep;11(9):936-43.