High expression of ubiquitin-specific protease 10 (USP10) promote the proliferation of hepatocellular carcinoma (HCC), thus the development of USP10 inhibitors holds promise as a novel therapeutic approach for HCC treatment. However, the development of selective USP10 inhibitor is still limited. In this study, we developed a novel USP10 inhibitor for investigating the feasibility of targeting USP10 for the treatment of HCC. Due to high USP10 inhibition potency and prominent selectivity, compound bearing quinolin-4(1)-one scaffold was identified as a lead compound. Subsequent research revealed that significantly inhibits cell proliferation and clone formation in HCC cells. Mechanistic insights indicated that targets the ubiquitin pathway, facilitating the degradation of YAP (Yes-associated protein), thereby triggering the downregulation of p53 and its downstream protein p21. Ultimately, this cascade leads to S-phase arrest in HCC cells, followed by cell apoptosis. Collectively, our findings highlight D1 as a promising starting point for USP10-positive HCC treatment, underscoring its potential as a vital tool for unraveling the functional intricacies of USP10.

中文翻译：

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通过调节 YAP 表达发现具有抗肝细胞癌活性的有效小分子泛素特异性蛋白酶 10 抑制剂


泛素特异性蛋白酶10（USP10）的高表达促进肝细胞癌（HCC）的增殖，因此USP10抑制剂的开发有望成为HCC治疗的新型治疗方法。然而，选择性USP10抑制剂的开发仍然有限。在本研究中，我们开发了一种新型 USP10 抑制剂，用于研究靶向 USP10 治疗 HCC 的可行性。由于具有高 USP10 抑制效力和显着的选择性，带有 quinolin-4(1)-one 支架的化合物被确定为先导化合物。随后的研究表明，显着抑制肝癌细胞的细胞增殖和克隆形成。机制研究表明，靶向泛素通路，促进 YAP（Yes 相关蛋白）的降解，从而触发 p53 及其下游蛋白 p21 的下调。最终，该级联导致 HCC 细胞 S 期停滞，随后细胞凋亡。总的来说，我们的研究结果强调 D1 作为 USP10 阳性 HCC 治疗的一个有希望的起点，强调了它作为解开 USP10 功能复杂性的重要工具的潜力。