A novel TNKS/USP25 inhibitor blocks the Wnt pathway to overcome multi-drug resistance in TNKS-overexpressing colorectal cancer.

Hongrui ZHU; Yamin GAO; Liyun LIU; Mengyu TAO; Xiao LIN; Yijia CHENG; Yaoyao SHEN; Haitao XUE; Li GUAN; Huimin ZHAO; Li LIU; Shuping WANG; Fan YANG; Yongjun ZHOU; Hongze LIAO; Fan SUN; Houwen LIN

Return

A novel TNKS/USP25 inhibitor blocks the Wnt pathway to overcome multi-drug resistance in TNKS-overexpressing colorectal cancer.

Author: Hongrui ZHU ¹ ; Yamin GAO ¹ ; Liyun LIU ¹ ; Mengyu TAO ² ; Xiao LIN ³ ; Yijia CHENG ¹ ; Yaoyao SHEN ¹ ; Haitao XUE ¹ ; Li GUAN ¹ ; Huimin ZHAO ¹ ; Li LIU ⁴ ; Shuping WANG ¹ ; Fan YANG ¹ ; Yongjun ZHOU ¹ ; Hongze LIAO ¹ ; Fan SUN ¹ ; Houwen LIN ¹
Author Information

1. Research Center for Marine Drugs, Department of Pharmacy, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China.
2. Department of Oncology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, China.
3. Institute of Marine Drugs, Guangxi University of Chinese Medicine, Nanning 530200, China.
4. State Key Laboratory of New Drug and Pharmaceutical Process, Shanghai Professional and Technical Ser-vice Center for Biological Material Drug-ability Evaluation, Shanghai Institute of Pharmaceutical Industry, China State Institute of Pharmaceutical Industry, Shanghai 200437, China.
Publication Type:Journal Article
Keywords: Apoptosis; Colorectal cancer; Multi-drug resistance; Neoantimycin analog; TNKS overexpression; TNKS–USP25 interaction; Wnt pathway
From: Acta Pharmaceutica Sinica B 2024;14(1):207-222
CountryChina
Language:English
Abstract: Modulating Tankyrases (TNKS), interactions with USP25 to promote TNKS degradation, rather than inhibiting their enzymatic activities, is emerging as an alternative/specific approach to inhibit the Wnt/β-catenin pathway. Here, we identified UAT-B, a novel neoantimycin analog isolated from Streptomyces conglobatus, as a small-molecule inhibitor of TNKS-USP25 protein-protein interaction (PPI) to overcome multi-drug resistance in colorectal cancer (CRC). The disruption of TNKS-USP25 complex formation by UAT-B led to a significant decrease in TNKS levels, triggering cell apoptosis through modulation of the Wnt/β-catenin pathway. Importantly, UAT-B successfully inhibited the CRC cells growth that harbored high TNKS levels, as demonstrated in various in vitro and in vivo studies utilizing cell line-based and patient-derived xenografts, as well as APC^min/+ spontaneous CRC models. Collectively, these findings suggest that targeting the TNKS-USP25 PPI using a small-molecule inhibitor represents a compelling therapeutic strategy for CRC treatment, and UAT-B emerges as a promising candidate for further preclinical and clinical investigations.