A potent, selective inhibitor of PI3-kinase γ
AS-252424 is a potent, selective and novel small-molecule PI3Kγ inhibitor (IC50= 30 nM)
PI3K (phosphatidylinositol-4,5-bisphosphate 3-kinase) is a family of enzymes involved in cellular functions such as cell growth, proliferation, differentiation, motility, survival and intracellular trafficking, which in turn are involved in cancer. It plays a key role in PI3K/Akt/mTOR pathway.
In THP-1 (human monocytic cell line), AS-252424 inhibited the phosphorylation of PKB/Akt due to MCP1 binding to the GPCR receptor CCR2 at lowest IC50 values of 0.4 μM. In primary monocytes and monocytic wild-type cell line THP-1, AS-252424 inhibited MCP-1-mediated chemotaxis in a concentration-dependent manner (IC50 value= 52 μM and 53 μM, respectively). [1] In Capan 1 and HPAF (pancreatic cancer cell lines), AS52424 specifically inhibited the cell proliferation. [2]
In a mouse model of thioglycollate-induced peritonitis, oral administration of AS-252424 at 10 mg/kg led to moderate reduction of neutrophil recruitment (35% ±14%). [1]
参考文献:
1. Pomel V, Klicic J, Covini D et al.?Furan-2-ylmethylene thiazolidinediones as novel, potent, and selective inhibitors of phosphoinositide 3-kinase gamma. J Med Chem. 2006 Jun 29;49(13):3857-71.
2.? Edling CE, Selvaggi F, Buus R et al. Key role of phosphoinositide 3-kinase class IB in pancreatic cancer. Clin Cancer Res. 2010 Oct 15;16(20):4928-37.
Kinase experiment: | A PI3Kγ lipid kinase assay, based on the neomycin-coated scintillation proximity assay (SPA) bead technology, is performed in 384-well plates using ATP/[γ33P]ATP and PtdIns. Kinase assays for IC50 value determinations with PI3Kα, PI3Kβ, and PI3Kδ are carried out[1]. |
Cell experiment: | After 3 h of starvation in serum-free medium, Raw-264 macrophages are pretreated with inhibitors (e.g., AS-252424, 1 nM, 10 nM, 100 nM, 1 μM, 10 μM and 100 μM) or DMSO for 30 min and stimulated for 5 min with 50 nM C5a. PKB/Akt phosphorylation is monitored using phospho-Ser-473 Akt specific antibody and standard ELISA protocols[1]. |
Animal experiment: | Mice[1]PI3Kγ knockout (KO) mice are used. Oral administration of AS-252424 at 10 mg/kg is performed in PI3Kγ-deficient mice. |
参考文献: [1]. Pomel V, et al. Furan-2-ylmethylene thiazolidinediones as novel, potent, and selective inhibitors of phosphoinositide 3-kinase gamma. J Med Chem. 2006 Jun 29;49(13):3857-71. | |
动态评分
0.0