产品描述:
AS-252424 is an inhibitor of PI3Kγ (IC50 = 0.03 µM) and long-chain acyl-CoA synthetase 4 (ACSL4).{14230,68714} It is selective for PI3Kγ over PI3Kα, PI3Kβ, and PI3Kδ (IC50s = 0.94, 20, and 20 µM, respectively) but also inhibits casein kinase 2 (CK2; IC50 = 0.02 µM). AS-252424 binds to the glutamine in position 464 of ACSL4 and inhibits ACSL4 enzymatic activity.{68714} It prevents decreases in viability induced by the ferroptosis inducer RSL3 in wild-type HT-1080 cells (IC50 = 2.2 µM) but not ACSL4 knockout HT-1080 cells, an effect that can be restored by re-expression of ACSL4. It also prevents RSL3-induced increases in lipid peroxidation in HT-1080 cells. Nanoparticles loaded with AS-252424 reduce inflammation and ferroptosis in an ACSL4-dependent manner in the kidney and liver in mouse models of renal ischemia-reperfusion injury induced by renal pedicle clamping and concanavalin A-induced acute liver injury, respectively. AS-252424 (0.5-2.5 µM) also reduces c-Kit ligand-induced production of leukotriene C4 (LTC4; Item No. 20210) and phosphorylation of cytosolic phospholipase A2 (cPLA2), JNK, and p38 MAPK in primary mouse bone marrow-derived mast cells.{68715} However, it increases airway hyperresponsiveness and airway smooth muscle thickening in a mouse model of toluene diisocyanate-induced asthma when administered at a dose of 10 mg/kg.{68716}