P3 - AG Becker Flegler Eyad Naser

Characterization of ARC39, a new inhibitor of acid sphingomyelinase

Acid sphingomyelinase (Asm), a lysosomal enzyme that catalyzes the hydrolysis of sphingomyelin into ceramide and phosphorylcholine, has been shown in preclinical studies to be a potential therapeutic target in several disease processes like cystic fibrosis, multiple sclerosis, autoimmune arthritis and hematogenous cancer metastasis. Specific and direct inhibitors of Asm are to this date not available. Functional inhibitors of Asm (FIASMAs), although many are clinically approved and well characterized, have many off-target effects and their use as Asm inhibitors is therefore promiscuous. The aim of this study is to characterize ARC39, a new bisphosphonate inhibitor of Asm, in vitro and in vivo. This includes establishing a range of effective doses, investigating possible off-target effects, excluding other mechanisms of Asm inhibition, determination of ARC39 specificity and investigating possible toxic effects in a dose- and time-dependent manner.