XMU-MP-1

A potent, selective, and ATP-competitive inhibitor of the mammalian Hippo orthologs, Sterile 20–like kinases MST1 and MST2 with IC50 of 71.1 nM and 38.1 nM, respectively; has a selectivity score of 0.05 against a panel of 468 diverse kinases; inhibits phosphorylation of MOB1 in a dose-dependent manner, activates the downstream effector Yes-associated protein (YAP) and promotes cell growth; attenuates acetaminophen-induced liver injury, promotes liver repair and regeneration in mice; a valuable chemical probe to study the Hippo signaling pathway (In Vitro) :At concentrations ranging from 0.1 to 10 μM, XMU-MP-1 reduces the phosphorylation of endogenous MOB1, LATS1/2, and YAP in HepG2 cells in a dose-dependent manner. XMU-MP-1 treatment inhibits hydrogen peroxide-stimulated MOB1 phosphorylation and MST1/2 autophosphorylation in a variety of cell lines, including mouse macrophage-like cells, human osteosarcoma, human colorectal adenocarcinoma cells. XMU-MP-1 blocks MST1/2 kinase activities, thereby activating the downstream effector Yes-associated protein and promoting cell growth. XMU-MP-1 can potently and reversibly suppress the activities of kinases MST1/2 and enhance their downstream YAP activation in cells. (In Vivo) :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. XMUMP-1 treatment exhibits 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.