Discovery of novel sphingosine kinase 1 inhibitorsvia structure-based hierarchical virtual screening

Abstract

Sphingosine kinase 1 (SphK1) is an oncogenic lipid kinase, emerging as a novel and promising target for cancer and other diseases. Herein, hierarchical structure-based virtual screening against the sphingosine kinase 1(SphK1) binding pocket was performed. Consequently, three compounds have been identified as dual inhibitors of SphK1 and SphK2. Among them, compound 25 exhibited comparable SphK1 and SphK2 inhibitory activities to the positive control N,N-dimethylsphingosine (DMS) 1, and exerted anti-proliferative effects on U937 cells. Furthermore, molecule dynamic (MD) simulations have been conducted to provide a more detailed insight into the binding model between SphK1 and 25 in a state close to physiological conditions. 25 may serve as a potential novel scaffold for further development of SphK1 inhibitors.