AS-252424

AS-252424 is an inhibitor of PI3Kγ (IC₅₀ = 0.03 µM) and long-chain acyl-CoA synthetase 4 (ACSL4).^1,2 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.² 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.³ 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.⁴

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1. Pomel, V., Klicic, J., Covini, D., et al. Furan-2-ylmethylene thiazolidinediones as novel, potent, and selective inhibitors of phosphoinositide 3-kinase γ. J. Med. Chem. 49(13), 3857-3871 (2006).

2. Huang, Q., Ru, Y., Luo, Y., et al. Identification of a targeted ACSL4 inhibitor to treat ferroptosis-related diseases. Sci. Adv. 10(13), eadk1200 (2024).

3. Jin, M., Zhou, Q., Lee, E., et al. AS252424, a PI3Kγ inhibitor, downregulates inflammatory responsiveness in mouse bone marrow-derived mast cells. Inflammation 37(4), 1254-1260 (2014).

4. Xu, C., Chen, S., Deng, Y., et al. Distinct roles of PI3Kδ and PI3Kγ in a toluene diisocyanate-induced murine asthma model. Toxicology 454, 152747 (2021).