Pharmacological targeting of kinases MST1 and MST2 augments tissue repair and regeneration
Pharmacological targeting of kinases MST1 and MST2 augments tissue repair and regeneration
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激酶 MST1 和 MST2 的药理学靶向增强组织修复和再生
DOI：
10.1126/scitranslmed.aaf2304
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发表时间：
2016-08-17
影响因子：
17.1
通讯作者：
Zhou, Dawang
中科院分区：
文献类型：
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作者：
Fan, Fuqin;He, Zhixiang;Zhou, Dawang
用Hippo激酶MST 1/2的可逆和选择性小分子抑制剂操纵Hippo信号传导通路为组织损伤和修复提供了治疗选择。药物诱导的再生弹出一个药丸来修复器官可能最终成为现实。从传统的支架，材料和基于细胞的再生医学策略转向，Fan和同事们寻求一种可以特异性靶向Hippo通路中关键信号分子的小分子。MST 1/2这一途径中激酶的缺失会增加发育过程中的细胞增殖;因此，作者假设抑制它们在成熟器官中的活性可以帮助修复任何损伤。他们发现了一种药物XMU-MP-1，可以阻断MST 1/2的活性，并发现它可以促进四种不同的急性和慢性损伤小鼠模型的肝脏修复和再生，包括对乙酰氨基酚诱导的损伤，这是全球肝功能衰竭的常见原因。与复杂的生物材料和细胞疗法相比，这种药理学策略可以使许多人的组织再生更容易。组织修复和再生医学解决了用功能组织替换受损组织的重要医疗需求。大多数再生医学策略都专注于提供生物材料和细胞，但药物诱导再生具有良好的特异性和安全性。Hippo通路通过抑制细胞增殖和促进细胞凋亡，是器官大小和再生的关键调节因子。激酶MST 1和MST 2（MST 1/2）是哺乳动物Hippo直系同源物，是该途径的核心组分，因此是ESTA诱导的组织再生的强靶候选物。我们报告了一种可逆的和选择性的MST 1/2抑制剂，4-（（5，10-二甲基-6-氧代-6，10-二氢-5H-嘧啶并[5，4-B]噻吩并[3，2-e][1，4]二氮杂卓-2-基）氨基）苯磺酰胺（XMU-MP-1）的发现，使用酶联免疫吸附测定为基础的高通量生化分析。共晶结构和构效关系证实XMU-MP-1是MST 1/2的靶向分子。XMU-MP-1阻断MST 1/2激酶活性，从而激活下游效应子Yes相关蛋白并促进细胞生长。XMU-MP-1显示出优异的体内药代动力学，并且能够在急性和慢性肝损伤小鼠模型中以1至3 mg/kg的剂量通过腹膜内注射增强小鼠肠修复以及肝修复和再生。XMU-MP-1处理在Fah缺陷小鼠模型中表现出比溶剂处理对照中显著更高的人肝细胞再增殖率，表明XMU-MP-1处理可能促进人肝再生。因此，MST 1/2激酶活性的药理学调节提供了一种增强组织修复和再生的新方法，其中XMU-MP-1是开发靶向再生疗法的第一个先导。
Manipulation of the Hippo signaling pathway with a reversible and selective small-molecule inhibitor of Hippo kinase MST1/2 provides a therapeutic option for tissue injury and repair. Drug-induced regeneration Popping a pill to repair an organ may eventually become reality. Turning away from conventional scaffolds, materials, and cell-based regenerative medicine strategies, Fan and colleagues sought a small molecule that could specifically target a critical signaling molecule in the Hippo pathway. Loss of kinases in this pathway, MST1/2, increases cell proliferation during development; thus, the authors hypothesized that inhibiting their activity in mature organs could help repair any damage. They discovered a drug, XMU-MP-1, that blocked MST1/2 activity and found that it promoted liver repair and regeneration in four different mouse models of acute and chronic injuries, including acetaminophen-induced injury, which is a common cause of liver failure worldwide. Such a pharmacological strategy could make tissue regeneration easier for many, compared to complex biomaterial and cell therapies. Tissue repair and regenerative medicine address the important medical needs to replace damaged tissue with functional tissue. Most regenerative medicine strategies have focused on delivering biomaterials and cells, yet there is the untapped potential for drug-induced regeneration with good specificity and safety profiles. The Hippo pathway is a key regulator of organ size and regeneration by inhibiting cell proliferation and promoting apoptosis. Kinases MST1 and MST2 (MST1/2), the mammalian Hippo orthologs, are central components of this pathway and are, therefore, strong target candidates for pharmacologically induced tissue regeneration. We report the discovery of a reversible and selective MST1/2 inhibitor, 4-((5,10-dimethyl-6-oxo-6,10-dihydro-5H-pyrimido[5,4-b]thieno[3,2-e][1,4]diazepin-2-yl)amino)benzenesulfonamide (XMU-MP-1), using an enzyme-linked immunosorbent assay–based high-throughput biochemical assay. The cocrystal structure and the structure-activity relationship confirmed that XMU-MP-1 is on-target to MST1/2. XMU-MP-1 blocked MST1/2 kinase activities, thereby activating the downstream effector Yes-associated protein and promoting cell growth. XMU-MP-1 displayed excellent in vivo pharmacokinetics and was 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.