Phosphatidylinositol-3-phosphate 5-kinase (PIKfyve) is a lipid kinase that synthesizes two phosphoinositides (PIs), regulating degradative and recycling endosomal trafficking, cytoskeletal rearrangement and autophagy. Apilimod Mesylate is a mesylate form of Apilimod. Apilimod is a 1,3,5-triazine derivative that binds to and inhibits PIKfyve kinase activity with an IC50 value of 14 nM. Treatment of apilimod (10 nM and 1 μM) for 120min decreased PI(3,5)P2 in HeLa cells at a dose-dependent manner. RAW264.7 cells treated with 10 nM Apilimod for 3h showed enlarged vacuoles due to the disruption of PIKfyve activity. In A549 cells, overexpression of wild-type PIKfyve resulted in the disappearance of vacuoles induced by 10 nM apilimod. Bone-marrow-derived dendritic cells from mutant mice demonstrated extensive vacuole formation with the treatment of 1 μM apilimod[3]. Apilimod showed selective antiproliferative activity in B-NHL cells with an IC50 value of 142 nM. After the treatment of 200 nM apilimod for 3 days, increased apoptosis was shown in SU-DHL-10 B-NHL cells. In a subcutaneous daudi burkitt lymphoma xenograft model, apilimod (50 - 150 mg/kg free base; p.o., once a day) displayed tumor growth inhibition at a dose-dependent manner. The growth inhibition was also observed in SU-DHL-6 DLBCL model treated with both apilimod (41 mg/kg free base, p.o., twice a day) and rituximab (7 mg/kg, i.p.)[4].
作用机制
Apilimod is a potent, highly selective PIKfyve inhibitor that binds to the PIKfyve domain (amino acids 1522 to 2098) to block the phosphotransferase activity of PIKfyve, thereby inhibiting IL-12/23p40[3].
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