Characterization of the small molecule ARC39, a direct and specific inhibitor of acid sphingomyelinase in vitro.

Journal of Lipid Research
Eyad NaserAlexander Carpinteiro

Abstract

Inhibition of acid sphingomyelinase (ASM), a lysosomal enzyme that catalyzes the hydrolysis of sphingomyelin into ceramide and phosphorylcholine, may serve as an investigational tool or a therapeutic intervention to control many diseases. Specific ASM inhibitors are currently not sufficiently characterized. Here, we found that 1-aminodecylidene bis-phosphonic acid (ARC39) specifically and efficiently (>90%) inhibits both lysosomal and secretory ASM in vitro. Results from investigating sphingomyelin phosphodiesterase 1 (SMPD1/Smpd1) mRNA and ASM protein levels suggested that ARC39 directly inhibits ASM's catalytic activity in cultured cells, a mechanism that differs from that of functional inhibitors of ASM. We further provide evidence that ARC39 dose- and time-dependently inhibits lysosomal ASM in intact cells, and we show that ARC39 also reduces platelet- and ASM-promoted adhesion of tumor cells. The observed toxicity of ARC39 is low at concentrations relevant for ASM inhibition in vitro, and it does not strongly alter the lysosomal compartment or induce phospholipidosis in vitro. When applied intraperitoneally in vivo, even subtoxic high doses administered short-term induced sphingomyelin accumulation only locally in the peri...Continue Reading

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Citations

Jun 2, 2020·Frontiers in Cellular and Infection Microbiology·Franziska SolgerThomas Rudel
Oct 14, 2020·Chemistry : a European Journal·Doaa SamahaChristoph Arenz
Nov 13, 2020·Chemical Communications : Chem Comm·Kevin PrauseChristoph Arenz

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Methods Mentioned

BETA
FCS
enzymatic assay
FRET
Assay
lavage
glycosylation
flow
flow cytometry
confocal microscopy

Software Mentioned

ImageQuant
GraphPad Prism
MassHunter
ChemDraw
GraphPad

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