Discovery of DPTIP a Small Molecule Inhibitor of Neutral Sphingomyelinase 2 (nSMase2) for the Treatment of Neurodegenerative and Oncologic Diseases

This technology includes a newly discovered molecule 2,6-Dimethoxy-4-(5-Phenyl-4-Thiophen-2-yl-1H-Imidazol-2-yl)-Phenol (DPTIP) as potent inhibitor of neutral sphingomyelinase 2 (nSMase2), to be used for the treatment of neurodegenerative and oncologic diseases. This discovery was identified through unbiased screening of the National Center for Advancing Chemical Sciences (NCATS) chemical library using our human neutral sphingomyelinase assay. DPTIP is a non-competitive inhibitor with respect to sphingomyelin, it inhibits exosome release both in vitro and in vivo, it is metabolically stable and it penetrates the brain (AUCbrain/AUCplasma = 0.26). Based upon genetic and pharmacological inhibition studies, DPTIP will have broad therapeutic utility in neurodegenerative and oncologic diseases wherein abnormal exosome secretion is presumed pathogenic.