Identification of α-Mangostin as a Potential Inhibitor of Microtubule Affinity Regulating Kinase 4

Microtubule affinity regulating kinase 4 (MARK4) is a potential drug target for neuronal disorders and several types of cancers. Filtration of naturally occurring compound libraries using high-throughput screening and enzyme assay suggest alpha-mangostin is a potential inhibitor of MARK4. Structure-based docking and 100 ns molecular dynamics simulation revealed that the binding of alpha-mangostin stabilizes the MARK4 structure. Enzyme inhibition and binding studies showed that alpha-mangostin inhibited MARK4 in the submicromolar range with IC50 = 1.47 mu M and binding constant (K-a) 5.2 x 10(7) M-1. Cell-based studies suggested that alpha-mangostin inhibited the cell viability (MCF-7 and HepG2), induced apoptosis, arrested the cell cycle in the G0/G1 phase, and reduced tau-phosphorylation. This study implicates MARK4 as a new target of alpha-mangostin, adding an additional lead molecule to the anticancer repertoire.