The mammalian ste20-like kinases 1/2 (MST1/2) which is a core component in the Hippo pathway in mammals, is related in cell growth, controlling organ size and maintaining organ homeostasis[1]. XMU-MP-1 is a potent and selective inhibitor of MST1/2 with IC50 value of 71.1 nM and 38.1 nM against MST1 and MST2, respectively[2]. XUM-MP-1 was added to a variety of cell lines including RAW264.7, USOS, SW480, SNU-423, RPE1 and HepG2, and the inhibition of hydrogen peroxide (H2O2)–stimulated MOB1 phosphorylation and MST1/2 autophosphorylation started at concentration of 1 and 3 μM for all cell lines measured by immunoblotting assay after incubating with XMU-MP-1 for 3 hours. In Sprague-Dawley rats, after intraperitoneal administration of 1 mg/kg XMU-MP-1, the maximal phosphorylation inhibition of MOB1 and YAP was achieved between 1.5 and 6 hours in the liver tissue. The wild-type mice were treated with XMU-MP-1 once a day before a two-thirds partial hepatectomy followed by daily treatment for 7 days. The treatment of XMU-MP-1 could enhance liver regeneration and increase the amounts of Ki67-positive cells and YAP-positive cells in the liver, as well as liver/body weight ratio compared with the control group.
作用机制
XMUMP-1 target the ATP-binding site of the kinases MST1/2.
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