Watkins Ryan, Gamo Ana, Choi Seung Hyuk, Kumar Manoj, Buckarma EeeLN, McCabe Chantal, Tomlinson Jennifer, Pereya David, Lupse Blaz, Geravandi Shirin, Werneburg Nathan W, Wang Chen, Starlinger Patrick, Zhu Siying, Li Sijia, Yu Shan, Surakattula Murali, Baguley Tyler, Ardestani Amin, Maedler Kathrin, Roland Jason, Nguyen-Tran Van, Joseph Sean, Petrassi Mike, Rogers Nikki, Gores Gregory, Chatterjee Arnab, Tremblay Matthew, Shen Weijun, Smoot Rory
Department of Surgery, Mayo Clinic, Rochester, MN 55905, USA.
Calibr at Scripps Research, The Scripps Research Institute, La Jolla, CA 92037, USA.
PNAS Nexus. 2024 Mar 1;3(3):pgae096. doi: 10.1093/pnasnexus/pgae096. eCollection 2024 Mar.
Dysfunctional liver regeneration following surgical resection remains a major cause of postoperative mortality and has no therapeutic options. Without targeted therapies, the current treatment paradigm relies on supportive therapy until homeostasis can be achieved. Pharmacologic acceleration of regeneration represents an alternative therapeutic avenue. Therefore, we aimed to generate a small molecule inhibitor that could accelerate liver regeneration with an emphasis on diseased models, which represent a significant portion of patients who require surgical resection and are often not studied. Utilizing a clinically approved small molecule inhibitor as a parent compound, standard medicinal chemistry approaches were utilized to generate a small molecule inhibitor targeting serine/threonine kinase 4/3 (MST1/2) with reduced off-target effects. This compound, mCLC846, was then applied to preclinical models of murine partial hepatectomy, which included models of diet-induced metabolic dysfunction-associated steatohepatitis (MASH). mCLC846 demonstrated on target inhibition of MST1/2 and reduced epidermal growth factor receptor inhibition. The inhibitory effects resulted in restored pancreatic beta-cell function and survival under diabetogenic conditions. Liver-specific cell-line exposure resulted in Yes-associated protein activation. Oral delivery of mCLC846 perioperatively resulted in accelerated murine liver regeneration and improved survival in diet-induced MASH models. Bulk transcriptional analysis of regenerating liver remnants suggested that mCLC846 enhanced the normal regenerative pathways and induced them following liver resection. Overall, pharmacological acceleration of liver regeneration with mCLC846 was feasible, had an acceptable therapeutic index, and provided a survival benefit in models of diet-induced MASH.
手术切除后肝脏再生功能障碍仍然是术后死亡的主要原因，且尚无治疗方法。在没有靶向治疗的情况下，当前的治疗模式依赖于支持性治疗，直到实现内环境稳定。药物促进再生是一种替代治疗途径。因此，我们旨在开发一种小分子抑制剂，该抑制剂能够加速肝脏再生，重点关注疾病模型，这类模型代表了需要手术切除且常未被研究的很大一部分患者。利用一种临床批准的小分子抑制剂作为母体化合物，采用标准药物化学方法来生成一种靶向丝氨酸/苏氨酸激酶4/3（MST1/2）且脱靶效应降低的小分子抑制剂。然后将该化合物mCLC846应用于小鼠部分肝切除的临床前模型，其中包括饮食诱导的代谢功能障碍相关脂肪性肝炎（MASH）模型。mCLC846表现出对MST1/2的靶向抑制作用，并减少了表皮生长因子受体抑制。这些抑制作用导致在致糖尿病条件下胰腺β细胞功能恢复和存活率提高。肝脏特异性细胞系暴露导致Yes相关蛋白激活。围手术期口服mCLC846可加速小鼠肝脏再生，并提高饮食诱导的MASH模型中的存活率。对再生肝残余物的大量转录分析表明，mCLC846增强了正常的再生途径，并在肝切除后诱导这些途径。总体而言，用mCLC846进行肝脏再生的药物促进是可行的，具有可接受的治疗指数，并在饮食诱导的MASH模型中提供生存益处。
