Identification of a new class of activators of the Hippo pathway with antitumor activity in vitro and in vivo

• Published in: Biochemical pharmacology Vol. 224; p. 116217
• Main Authors: Lin, Guifeng, Xia, Anjie, Qiao, Jingxin, Zhang, Hailin, Chen, Pei, Zhou, Pei, Hu, Qian, Xiang, Zhiyu, Zhang, Shiyu, Li, Linli, Yang, Shengyong
• Format: Journal Article
• Language: English
• Published: England Elsevier Inc 01-06-2024
• Subjects: Animals; Anti-cancer; Antineoplastic Agents - pharmacology; Apoptosis - drug effects; Cell Line, Tumor; Connective Tissue Growth Factor - genetics; Connective Tissue Growth Factor - metabolism; Drug discovery; Female; Hippo Signaling Pathway; Humans; Mice; Mice, Inbred BALB C; Mice, Nude; Pancreatic cancer; Protein Serine-Threonine Kinases - metabolism; Signal Transduction - drug effects; Signal Transduction - physiology; Small molecular activator; Structural optimization; The Hippo pathway; Xenograft Model Antitumor Assays - methods; STRIPAK; DMSO; YAP; TAZ; ATCC; CYR61; RIPA; CTGF; STR; DMEM; LATS1 and LATS2; Structural optimization; ANOVA; FBS; EC50; RUNX1/2; RLU; SMAD; Anti-cancer; MAP4Ks; MST1 and MST2; H&E; EMT; LD50; TEAD; TAOKs; MOB1; Pancreatic cancer; GPCR; Drug discovery; Small molecular activator; qRT–PCR; The Hippo pathway; TAOKi
• ISSN: 0006-2952; 1873-2968; 1873-2968
• DOI: 10.1016/j.bcp.2024.116217

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The Hippo pathway is a key regulator of tissue growth, organ size, and tumorigenesis. Activating the Hippo pathway by gene editing or pharmaceutical intervention has been proven to be a new therapeutic strategy for treatment of the Hippo pathway-dependent cancers. To now, a number of compounds that directly target the downstream effector proteins of Hippo pathway, including YAP and TEADs, have been disclosed, but very few Hippo pathway activators are reported. Here, we discovered a new class of Hippo pathway activator, YL-602, which inhibited CTGF expression in cells irrespective of cell density and the presence of serum. Mechanistically, YL-602 activates the Hippo pathway via MST1/2, which is different from known activators of Hippo pathway. In vitro, YL-602 significantly induced tumor cell apoptosis and inhibited colony formation of tumor cells. In vivo, oral administration of YL-602 substantially suppressed the growth of cancer cells by activation of Hippo pathway. Overall, YL-602 could be a promising lead compound, and deserves further investigation for its mechanism of action and therapeutic applications.