XMU-MP-1 is a reversible and selective inhibitor of MST1/2 kinase, with IC50s of 71.1±12.9 nM and 38.1±6.9 nM for MST1 and MST2 respectively[1]. XMU-MP-1 can promote the activation of the downstream effector YAP (Yes-associated protein), which has the effects of promoting cell proliferation, tissue repair and regeneration [2].
In vitro, XMU-MP-1 (0.1 to 10 μM) treated HepG2 cells for 3 h and reduced the phosphorylation of endogenous MOB1, LATS1/2 and YAP in the cells in a dose-dependent manner[1]. XMU-MP-1 (1-5μM) treated neonatal rat cardiomyocytes for 24 h, significantly enhanced the YAP luciferase activity in the cells and reduced the phosphorylation of MOB kinase activator 1 (MOB1) [3]. XMU-MP-1 (3 μM) treated human hair follicles for 24 h, resulting in a reduction in the proportion of proliferating cells, an increase in Ki-67 protein expression, a decrease in active YAP1 immunoreactivity in the anterior cortex of hair follicles, and a decrease in phosphate in the hair follicle matrix and anterior cortex. chemMOB1 (Thr35) immunoreactivity [4].
In vivo, XMU-MP-1 (1mg/kg) was treated with osteoarthritis mice by intraperitoneal injection for 2 weeks, inhibiting the erosion of the articular cartilage surface, synovial thickening, and blocking the ECM components in the cartilage caused by DMM surgery ( The reduction of type II collagen) and the increase of the expression of matrix-degrading enzyme MMP13 alleviate osteoarthritis[5]. XMU-MP-1 (1mg/kg) was treated intraperitoneally for 7 days in mice injured by infrared radiation. It can rescue the damage caused by infrared rays to the hematopoietic system, reduce the ROS level of the hematopoietic system, and prevent damage to the small intestinal system [6].
References:
[1] Fan F, He Z, Kong L L, et al. Pharmacological targeting of kinases MST1 and MST2 augments tissue repair and regeneration[J]. Science translational medicine, 2016, 8(352): 352ra108-352ra108.
[2] Liu Y, Chu G, Shen W, et al. XMU-MP-1 protects heart from ischemia/reperfusion injury in mice through modulating Mst1/AMPK pathway[J]. European Journal of Pharmacology, 2022, 919: 174801.
[3] Triastuti E, Nugroho A B, Zi M, et al. Pharmacological inhibition of Hippo pathway, with the novel kinase inhibitor XMU‐MP‐1, protects the heart against adverse effects during pressure overload[J]. British journal of pharmacology, 2019, 176(20): 3956-3971.
[4] Mitchell E, Mellor C E L, Purba T S. XMU-MP-1 induces growth arrest in a model human mini-organ and antagonises cell cycle-dependent paclitaxel cytotoxicity[J]. Cell Division, 2020, 15: 1-6.
[5] Hao X, Zhao J, Jia L, et al. XMU-MP-1 attenuates osteoarthritis via inhibiting cartilage degradation and chondrocyte apoptosis[J]. Frontiers in Bioengineering and Biotechnology, 2022, 10: 998077.
[6] Zhou X, Wang H, Li D, et al. MST1/2 inhibitor XMU‐MP‐1 alleviates the injury induced by ionizing radiation in haematopoietic and intestinal system[J]. Journal of Cellular and Molecular Medicine, 2022, 26(5): 1621-1628.
XMU-MP-1是可逆的、选择性的MST1/2激酶的抑制剂，对MST1和MST2的IC50分别为71.1±12.9 nM和38.1±6.9 nM[1]。XMU-MP-1能够促进下游效应器YAP（Yes-associated protein）的激活，具有促进细胞增殖、组织修复和再生等作用[2]。
在体外，XMU-MP-1（0.1 to 10μM）处理HepG2细胞3 h，以剂量依赖性方式降低了细胞中内源性MOB1、LATS1/2和YAP的磷酸化[1]。XMU-MP-1（1-5μM）处理新生大鼠心肌细胞24 h，显著增强了细胞中的YAP荧光素酶活性，降低了MOB激酶激活剂1（MOB1）的磷酸化[3]。XMU-MP-1（3μM）处理人毛囊24 h，造成了增殖细胞比例减少，Ki-67蛋白表达增加，降低毛囊前皮质中的活性YAP1免疫反应性，并降低毛囊基质和前皮质中的磷酸化MOB1（Thr35）免疫反应性[4]。
在体内，XMU-MP-1（1mg/kg）通过腹腔注射治疗骨关节炎小鼠2周，抑制了关节软骨表面的侵蚀、滑膜增厚，阻断了DMM手术引起的软骨中ECM成分（II型胶原）的减少和基质降解酶MMP13表达的升高，减轻了骨关节炎[5]。XMU-MP-1（1mg/kg）通过腹腔注射治疗红外辐射损伤的小鼠7天，可挽救红外线对造血系统造成的损伤，降低造血系统ROS水平，还阻止了小肠系统损伤[6]。