AS-252424

AS-252424 is a potent and selective PI3Kγ inhibitor with an IC₅₀ of 30±10 nM. IC50 & Target: IC50: 30±10 nM (PI3Kγ), 935±150 nM (PI3Kα), 20 μM (PI3Kβ), 20 μM (PI3Kδ)^[1] In Vitro: AS-252424 also inhibits PI3Kα, PI3Kβ and PI3Kδ with IC₅₀s of 935±150 nM, 20 μM and 20 μM, respectively. AS-252424 inhibits MCP-1-mediated chemotaxis in wild-type primary monocytes in a concentration-dependent manner with an IC₅₀ value of 52 μM, as well as in the monocytic cell line THP-1 with an IC₅₀ value of 53 μM. In the human monocytic cell line THP-1, MCP-1 binding to the GPCR chemokine receptor CCR2, strongly induces phosphorylation of PKB/Akt, which is effectively inhibited by AS-252424 at IC₅₀ values as low as 0.4 μM. In contrast, induction of PKB/Akt phosphorylation by colony stimulating factor (CSF-1), binding to the growth factor receptor c-fms, is only blocked by AS-252424 at IC₅₀ values as high as 4.7 μM^[1]. In Vivo: Oral administration of AS-252424 in a mouse model of acute peritonitis leads to a significant reduction of leukocyte recruitment. To evaluate the efficacy of AS-252424 to block leukocyte migration in vivo, it is tested in a mouse model of thioglycollate-induced peritonitis. Oral administration of AS-252424 at 10 mg/kg results in moderate reduction of neutrophil recruitment (35%±14%), almost matching the result observed in PI3Kγ-deficient mice. Given the short oral half-life of AS-252424 (t_1/2=1 h) and relative high clearance (2.25 L/kg per h), investigations at later time points (24-48 h) to assess macrophage and monoycyte recruitment are not undertaken. The modest pharmacokinetic properties do not appear to be caused by rapid oxidative metabolism (microsomal metabolism after 1 h: 16% (rat), 10% (human))^[1].