Xiao Chen, Wu Zhenhua, Liao Liuqi, Shi Chao, Gao Huan, Zhang Ting, Chen Qinghua, Hou Yongqiang, Yun Cai-Hong, Su Dongxue, Zhou Dawang, Deng Xianming, Chen Lanfen
State Key Laboratory of Cellular Stress Biology, Xiang'an Hospital, School of Life Sciences, Xiamen University, Xiamen, China.
Department of Biophysics, School of Basic Medical Sciences, Peking University, Beijing, China.
Br J Pharmacol. 2025 Jul 22. doi: 10.1111/bph.70137.
Large tumor suppressor kinases (LATS1 and 2) are core kinases of the Hippo signalling pathway, directly phosphorylate and inactivate the transcriptional coactivator Yes-associated protein 1 (YAP), playing a pivotal role in cell self-renewal and tissue regeneration. Hippo signalling inhibitors are urgently needed, both as tools for pharmacological studies of the Hippo pathway and as leads for developing novel, molecularly targeted drugs for the treatment of tissue injury and regeneration.
An enzyme linked immunosorbent assay (ELISA)-based in vitro high-throughput biochemical assay was used to the identification of a potent and reversible LATS1/2 inhibitor, N-(2-chloro-6-fluorobenzyl)-5-(1H-pyrrolo[2,3-b] pyridin-3-yl) furan-3-carboxamide (named as LPi-1). The regulation of LPi-1 on the activity of LATS1/2 kinases and YAP was evaluated both in vitro and in vivo. The murine models, including partial hepatectomy, paracetamol (acetaminophen/APAP)-induced liver hepatotoxicity and chemically induced colitis, were established to investigate the effect of LPi-1 on tissue repair and regeneration after injuries.
LPi-1 effectively inhibited the activity of LATS1/2 kinases, thereby facilitating YAP activation to enhance the proliferation of hepatocytes in vitro. Moreover, LPi-1 was able to augment intestinal repair in mice following dextran sulphate sodium salt (DSS) treatment, as well as liver repair and regeneration in mice subjected to two-thirds partial hepatectomy or APAP-induced liver injury.
In conclusion, LPi-1 can serve as a valuable tool compound for exploring diverse biological functions associated with LATS1/2 kinases, as well as a promising lead compound for developing targeted therapeutic strategies aimed at enhancing tissue repair and regeneration.
大肿瘤抑制激酶（LATS1和LATS2）是Hippo信号通路的核心激酶，直接磷酸化并失活转录共激活因子Yes相关蛋白1（YAP），在细胞自我更新和组织再生中起关键作用。迫切需要Hippo信号通路抑制剂，既作为Hippo通路药理学研究的工具，也作为开发用于治疗组织损伤和再生的新型分子靶向药物的先导化合物。
基于酶联免疫吸附测定（ELISA）的体外高通量生化测定法用于鉴定一种强效且可逆的LATS1/2抑制剂N-（2-氯-6-氟苄基）-5-（1H-吡咯并[2,3-b]吡啶-3-基）呋喃-3-甲酰胺（命名为LPi-1）。在体外和体内评估了LPi-1对LATS1/2激酶和YAP活性的调节作用。建立了包括部分肝切除术、对乙酰氨基酚（扑热息痛/APAP）诱导的肝毒性和化学诱导的结肠炎在内的小鼠模型，以研究LPi-1对损伤后组织修复和再生的影响。
LPi-1有效抑制LATS1/2激酶的活性，从而促进YAP激活，增强体外肝细胞的增殖。此外，LPi-1能够增强硫酸葡聚糖钠盐（DSS）处理后小鼠的肠道修复，以及三分之二部分肝切除或APAP诱导的肝损伤小鼠的肝脏修复和再生。
总之，LPi-
