Abstract

Hippo signalling pathway plays a crucial role in tumorigenesis and cancer progression. In this work, we identified an N-aryl sulphonamide-quinazoline derivative, compound 9i as an anti-gastric cancer agent, which exhibited potent antiproliferative ability with IC₅₀ values of 0.36 μM (MGC-803 cells), 0.70 μM (HCT-116 cells), 1.04 μM (PC-3 cells), and 0.81 μM (MCF-7 cells), respectively and inhibited YAP activity by the activation of p-LATS. Compound 9i was effective in suppressing MGC-803 xenograft tumour growth in nude mice without obvious toxicity and significantly down-regulated the expression of YAP in vivo. Compound 9i arrested cells in the G2/M phase, induced intrinsic apoptosis, and inhibited cell colony formation in MGC-803 and SGC-7901 cells. Therefore, compound 9i is to be reported as an anti-gastric cancer agent via activating the Hippo signalling pathway and might help foster a new strategy for the cancer treatment by activating the Hippo signalling pathway regulatory function to inhibit the activity of YAP.

 抽象的

Hippo信号通路在肿瘤发生和癌症进展中发挥着至关重要的作用。在这项工作中，我们鉴定了一种N-芳基磺酰胺-喹唑啉衍生物（化合物9i）作为抗胃癌药物，它表现出有效的抗增殖能力，IC ₅₀值为 0.36 μM（MGC-803 细胞）、0.70 μM（HCT-116）分别为 1.04 μM（PC-3 细胞）和 0.81 μM（MCF-7 细胞），并通过激活 p-LATS 抑制 YAP 活性。化合物9i能有效抑制裸鼠MGC-803异种移植瘤的生长，且无明显毒性，并显着下调体内YAP的表达。化合物9i将细胞阻滞在G2/M期，诱导内在细胞凋亡，并抑制MGC-803和SGC-7901细胞中的细胞集落形成。因此，化合物9i将被报道为通过激活Hippo信号通路的抗胃癌药物，并可能通过激活Hippo信号通路调节功能抑制YAP活性来帮助培育癌症治疗的新策略。