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

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 displays excellent in in vivo pharmacokinetics and is able to augment mouse intestinal repair, as well as liver repair and regeneration, in both acute and chronic liver injury mouse models at a dose of 1 to 3 mg/kg via intraperitoneal injection. XMU-MP-1 treatment exhibited substantially greater repopulation rate of human hepatocytes in the Fah-deficient mouse model than in the vehicle-treated control, indicating that XMU-MP-1 treatment might facilitate human liver regeneration. Thus, the pharmacological modulation of MST1/2 kinase activities provides a novel approach to potentiate tissue repair and regeneration, with XMU-MP-1 as the first lead for the development of 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].