Identification of YL064 as a novel inhibitor of ATXN3 to suppress tumor growth and metastasis by promoting degradation of oncogenic substrates.
6 affiliations
- 1Department of Hematology, Tongren Hospital & Department of Pathophysiology, Key Laboratory of Cell Differentiation and Apoptosis of the National Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
- 2School of Pharmaceutical Sciences, Shanghai Jiao Tong University, Shanghai, China.
- 3State Key Laboratory of Coordination Chemistry and Jiangsu Key Laboratory of Advanced Organic Materials, School of Chemistry and Chemical Engineering, Nanjing University, Nanjing, China.
- 4Department of Oral and Maxillofacial-Head and Neck Oncology, Ninth People's Hospital, College of Stomatology, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
- 5Department of Hematology, Tongren Hospital & Department of Pathophysiology, Key Laboratory of Cell Differentiation and Apoptosis of the National Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai, China. [email protected].
- 6Department of Hematology, Tongren Hospital & Department of Pathophysiology, Key Laboratory of Cell Differentiation and Apoptosis of the National Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai, China. [email protected].
Abstract
ATXN3 has recently emerged as a pro-oncogenic deubiquitinating enzyme (DUB) involved in the progression of multiple cancers, including breast and prostate cancer. However, the therapeutic potential of targeting ATXN3 remains largely unexplored due to the lack of effective inhibitors. In this study, we performed an Ub-AMC-based high-throughput screening assay using full-length ATXN3 and identified YL064, a derivative of the natural product sinomenine isolated from Sinomenium acutum, as a novel ATXN3 inhibitor. Direct interaction between YL064 and ATXN3 was confirmed by thermal shift assay, cellular thermal shift assay, surface plasmon resonance, and molecular docking analysis. Functionally, YL064 suppressed cancer cell proliferation, induced cell-cycle arrest, and reduced metastatic potential. Mechanistically, YL064 inhibited ATXN3 deubiquitinating activity and promoted the ubiquitination and proteasomal degradation of ATXN3 substrates, including KLF4 and YAP. Furthermore, YL064 significantly inhibited tumor growth in an orthotopic breast cancer model in vivo. Collectively, our findings establish YL064 as a promising ATXN3 inhibitor that targets the ubiquitin-proteasome pathway to exert anti-tumor effects, highlighting its potential as a novel therapeutic agent for ATXN3-driven cancers.
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BibTeX
@article{zhang2026identification,
title = {{Identification of YL064 as a novel inhibitor of ATXN3 to suppress tumor growth and metastasis by promoting degradation of oncogenic substrates.}},
author = {Zhenge Zhang and Wenhui Bai and Yayue Tan and Guanyi Li and Youping Zhang and Wenxuan Wu and Chujiao Zhu and Xingyu Liu and Manyu Zhang and Hu Lei and Hanzhang Xu and Li Yang and Ligen Liu and Yaxue Zhao and Zhujun Yao and Qi Zhu and Yingying Wang and Yingli Wu},
journal = {Cell death \& disease},
year = {2026},
month = aug,
doi = {10.1038/s41419-026-09171-5},
url = {https://europepmc.org/article/MED/42971951},
note = {CC BY},
}
RIS
TY - JOUR
TI - Identification of YL064 as a novel inhibitor of ATXN3 to suppress tumor growth and metastasis by promoting degradation of oncogenic substrates.
AU - Zhenge Zhang
AU - Wenhui Bai
AU - Yayue Tan
AU - Guanyi Li
AU - Youping Zhang
AU - Wenxuan Wu
AU - Chujiao Zhu
AU - Xingyu Liu
AU - Manyu Zhang
AU - Hu Lei
AU - Hanzhang Xu
AU - Li Yang
AU - Ligen Liu
AU - Yaxue Zhao
AU - Zhujun Yao
AU - Qi Zhu
AU - Yingying Wang
AU - Yingli Wu
PY - 2026
DA - 2026/08/06
JO - Cell death & disease
DO - 10.1038/s41419-026-09171-5
UR - https://europepmc.org/article/MED/42971951
AB - ATXN3 has recently emerged as a pro-oncogenic deubiquitinating enzyme (DUB) involved in the progression of multiple cancers, including breast and prostate cancer. However, the therapeutic potential of targeting ATXN3 remains largely unexplored due to the lack of effective inhibitors. In this study, we performed an Ub-AMC-based high-throughput screening assay using full-length ATXN3 and identified YL064, a derivative of the natural product sinomenine isolated from Sinomenium acutum, as a novel ATXN3 inhibitor. Direct interaction between YL064 and ATXN3 was confirmed by thermal shift assay, cellular thermal shift assay, surface plasmon resonance, and molecular docking analysis. Functionally, YL064 suppressed cancer cell proliferation, induced cell-cycle arrest, and reduced metastatic potential. Mechanistically, YL064 inhibited ATXN3 deubiquitinating activity and promoted the ubiquitination and proteasomal degradation of ATXN3 substrates, including KLF4 and YAP. Furthermore, YL064 significantly inhibited tumor growth in an orthotopic breast cancer model in vivo. Collectively, our findings establish YL064 as a promising ATXN3 inhibitor that targets the ubiquitin-proteasome pathway to exert anti-tumor effects, highlighting its potential as a novel therapeutic agent for ATXN3-driven cancers.
SN - 2041-4889
ER -