The YAP/Hippo pathway is an organ growth and size regulation rheostat safeguarding multiple tissue stem cell compartments. LATS kinases phosphorylate and thereby inactivate YAP, thus representing a potential direct drug target for promoting tissue regeneration. Here, we report the identification and characterization of the selective small-molecule LATS kinase inhibitor NIBR-LTSi. NIBR-LTSi activates YAP signaling, shows good oral bioavailability, and expands organoids derived from several mouse and human tissues. In tissue stem cells, NIBR-LTSi promotes proliferation, maintains stemness, and blocks differentiation in vitro and in vivo. NIBR-LTSi accelerates liver regeneration following extended hepatectomy in mice. However, increased proliferation and cell dedifferentiation in multiple organs prevent prolonged systemic LATS inhibition, thus limiting potential therapeutic benefit. Together, we report a selective LATS kinase inhibitor agonizing YAP signaling and promoting tissue regeneration in vitro and in vivo, enabling future research on the regenerative potential of the YAP/Hippo pathway.

YAP/Hippo 通路是一种器官生长和大小调节变阻器，可保护多个组织干细胞区室。 LATS 激酶磷酸化，从而使 YAP 失活，因此代表了促进组织再生的潜在直接药物靶点。在这里，我们报告了选择性小分子 LATS 激酶抑制剂 NIBR-LTSi 的鉴定和表征。 NIBR-LTSi 激活 YAP 信号传导，显示出良好的口服生物利用度，并扩展源自多种小鼠和人体组织的类器官。在组织干细胞中，NIBR-LTSi在体外和体内促进增殖、维持干细胞性并阻止分化。 NIBR-LTSi 可加速小鼠肝切除术后的肝再生。然而，多个器官中增殖和细胞去分化的增加阻止了长期的全身性 LATS 抑制，从而限制了潜在的治疗益处。我们共同报道了一种选择性 LATS 激酶抑制剂，该抑制剂可激动 YAP 信号传导并促进体外和体内组织再生，从而为未来研究 YAP/Hippo 途径的再生潜力奠定了基础。