A small molecule MST1/2 inhibitor accelerates murine liver regeneration with improved survival in models of steatohepatitis

Watkins, Ryan; Gamo, Ana; Choi, Seung Hyuk; Kumar, Manoj; Buckarma, Eee LN; 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; Chatterjee, Arnab; Gores, Gregory; Tremblay, Matthew; Shen, Weijun; Smoot, Rory

Abstract

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.

Citation

Watkins, R., Gamo, A., Choi, S. H., Kumar, M., Buckarma, E. L., McCabe, C., Tomlinson, J., Pereya, D., Lupse, B., Geravandi, S., Werneburg, N. W., Wang, C., Starlinger, P., Zhu, S., Li, S., Yu, S., Surakattula, M., Baguley, T., Ardestani, A., Maedler, K., …Smoot, R. (2024). A small molecule MST1/2 inhibitor accelerates murine liver regeneration with improved survival in models of steatohepatitis. PNAS Nexus, 3(3), Article pgae096. https://doi.org/10.1093/pnasnexus/pgae096

• Journal Article Type: Article
• Acceptance Date: Feb 20, 2024
• Online Publication Date: Mar 1, 2024
• Publication Date: Mar 1, 2024
• Deposit Date: Aug 31, 2024
• Publicly Available Date: Sep 2, 2024
• Journal: PNAS Nexus
• Print ISSN: 2752-6542
• Electronic ISSN: 2752-6542
• Publisher: National Academy of Sciences
• Peer Reviewed: Peer Reviewed
• Volume: 3
• Issue: 3
• Article Number: pgae096
• DOI: https://doi.org/10.1093/pnasnexus/pgae096
• Keywords: Hippo; Medicinal chemistry; MASH; YAP; TAZ
• Public URL: https://hull-repository.worktribe.com/output/4619400