浙江大学杨波课题组近日取得一项新成果。经过不懈努力，他们的最新研究提出了基孔肯雅病毒抑制剂AKOS作为USP14抑制剂治疗结直肠癌的鉴定。2025年7月17日，国际知名学术期刊《中国药理学报》发表了这一成果。

在这项研究中，该课题组研究人员筛选了670个共价化合物进行体外Ub-AMC水解试验，并鉴定出AKOS（最初是基孔肯雅病毒抑制剂）是一种新的USP14小分子抑制剂。结果表明，AKOS抑制USP14去泛素酶活性的IC50值为0.98 μM。AKOS直接与USP14结合，共价修饰活性位点半胱氨酸残基（Cys114），从而有效抑制其去泛素酶活性。该团队证明AKOS抑制USP14可能会破坏MEF2D（一种关键底物）的稳定，导致ECM相关转录因子（如ITGB4）的表达和翻译下调。AKOS表现出强大的抗癌作用：USP14抑制剂在体外显著抑制结直肠癌细胞的增殖和转移，IC50值分别为9.88和16.57在SW620细胞和HCT116细胞中分别表达μM。肿瘤内注射AKOS (15,30 mg/kg，每5天)在体内有效抑制了HCT116异种移植异体模型的肿瘤生长。总之，课题组人员证明AKOS是一种很有前途的靶向USP14的CRC化学探针，为破坏CRC的恶性进展提供了一种新的策略。

据悉，泛素特异性蛋白酶14 （USP14）是调节蛋白酶体功能和细胞蛋白酶平衡的重要分子，在包括结直肠癌（CRC）在内的多种肿瘤的发生发展中起重要作用。

附：英文原文

Title: Identification of AKOS, a Chikungunya virus inhibitor, as a USP14 inhibitor for colorectal cancer treatment

Author: Lu, Bin, Sun, Yi-yun, Zhou, Jia-hao, Chen, Dan-ni, Guo, Yue, Chen, Yu-lu, Pan, Cheng-hao, Chen, Zheng-yang, He, Qiao-jun, Yuan, Meng, Cao, Ji, Jiang, Li, Yang, Bo

Issue&Volume: 2025-07-17

Abstract: Ubiquitin-specific protease 14 (USP14) is a crucial modulator of proteasomal function and cellular proteostasis, which plays an important role in the development and progression of various cancers including colorectal cancer (CRC). In this study we screened 670 covalent compounds using the in vitro Ub-AMC hydrolysis assay, and identified AKOS, initially a Chikungunya virus inhibitor, as a novel small-molecule inhibitor of USP14. We showed that AKOS inhibiting USP14 deubiquitinase activity with an IC50 value of 0.98 μM. AKOS directly bound to USP14, covalently modifying the active-site cysteine residue (Cys114), thereby effectively inhibiting its deubiquitinase activity. We demonstrated that inhibition of USP14 by AKOS might destabilize MEF2D, a critical substrate, resulting in downregulation of the expression and translation of ECM-related transcription factors such as ITGB4. AKOS exhibited potent anti-cancer effects: the USP14 inhibitor significantly inhibited the proliferation and metastasis of CRC cells in vitro with IC50 values of 9.88 and 16.57μM, respectively, in SW620 cells and HCT116 cells. Intratumoral injection of AKOS (15, 30mg/kg, every 5 days) effectively suppressed the tumor growth in HCT116 xenograft mouse models in vivo. Collectively, we demonstrate that AKOS is a promising chemical probe for targeting USP14 in CRC, offering a novel strategy for disrupting the malignant progression of CRC.

DOI: 10.1038/s41401-025-01616-5

Source: https://www.nature.com/articles/s41401-025-01616-5