XMU-MP-1 is an inhibitor of the pro-apoptotic, sterile 20-like kinases MST1 and 2.

MST2:38.1 nM, MST1:71.1 nM

XMU-MP-1 effectively reduces the phosphorylation of MOB1, LATS1/2, and YAP in HepG2 cells in a concentration-dependent manner, with effective doses ranging from 0.1 to 10 μM. It also inhibits MOB1 phosphorylation induced by hydrogen peroxide and prevents MST1/2 autophosphorylation across various cell lines, including mouse macrophage-like cells, human osteosarcoma, and human colorectal adenocarcinoma cells. By blocking MST1/2 kinase activities, XMU-MP-1 activates the downstream effector, Yes-associated protein (YAP), thereby promoting cell growth. Its action potently and reversibly suppresses the activities of MST1/2 kinases, enhancing YAP activation in cells.

XMU-MP-1 demonstrates excellent in vivo pharmacokinetics and enhances intestinal repair, as well as liver repair and regeneration, in both acute and chronic liver injury mouse models at doses of 1 to 3 mg/kg via intraperitoneal injection. In the Fah-deficient mouse model, XMU-MP-1 treatment significantly increased the repopulation rate of human hepatocytes compared to the vehicle-treated control, suggesting it may facilitate human liver regeneration. Therefore, pharmacological modulation of [MST1/2] kinase activities offers a novel method to enhance tissue repair and regeneration, with XMU-MP-1 as the initial lead for developing targeted regenerative therapeutics.

XMU-MP-1 is dissolved in DMSO (stock concentration, 10 mM). For the in vitro kinase inhibition assays, recombinant GST-tagged MOB1a and various forms of recombinant His-tagged full-length MST1 or MST2 kinase are expressed and purified from Escherichia coli. The assays are performed with the various doses of XMU-MP-1 in the kinase assay buffer for 30 min at 30°C[1].