2. Academic Validation
  3. USP5 inhibition enables potential therapy for t(8;21) AML through ubiquitin-mediated AML1-ETO degradation in patient-derived xenografts

USP5 inhibition enables potential therapy for t(8;21) AML through ubiquitin-mediated AML1-ETO degradation in patient-derived xenografts

  • Sci Transl Med. 2025 Sep 24;17(817):eadt9100. doi: 10.1126/scitranslmed.adt9100.
Lan Ma 1,  Kun Zhang 1,  Zixuan Zhang 1 2,  Chenyang Wang 1,  Mengyuan Ma 1,  Ying Liu 1,  Yanli Zhao 1,  Ziqing Gong 1,  Ning Liu 1,  Mingming Wei 1,  Xiang Liu 1,  Jingfeng Zhou 3,  Shuangwei Liu 1,  Cheng Yang 1,  Guang Yang 1
Affiliations

Affiliations

  • 1 State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, School of Life Sciences, Nankai University, Tianjin 300071, P. R. China.
  • 2 Department of Chemical and Environmental Engineering, Faculty of Science and Engineering, University of Nottingham, Ningbo 315100, P. R. China.
  • 3 International Cancer Center, School of Basic Medical Sciences, Department of Hematology and Oncology, Shenzhen University General Hospital, Shenzhen University Health Science Center, Shenzhen University, Nanshan District, Shenzhen, Guangdong 518055, P. R. China.
PMID: 40991730 DOI: 10.1126/scitranslmed.adt9100
Abstract

The AML1-ETO (AE) fusion protein is a key target for treating t(8;21) acute myeloid leukemia (AML). In this investigation, we identified Ubiquitin-Specific Protease 5 (USP5) as the deubiquitinating enzyme of AE. USP5 knockdown decreased AML cell growth and induced differentiation both in vitro and in vivo. In addition, we developed a high-throughput screening (HTS) method and identified a potent, selective USP5 inhibitor, WCY-8-67. This lead compound was identified as a selective USP5 inhibitor by targeting the ubiquitin-associated domain 2 (UBA2) region. It also induced aggregation and precipitation of the target protein, which led to USP5 dysfunction. WCY-8-67 exhibited excellent in vivo bioavailability and tolerability, and it effectively inhibited the growth of AML cells in animal models. In addition, in a patient-derived xenograft (PDX) model, this compound, when combined with 5-azacytidine (5-Aza), improved therapeutic effects. This study presents promising targeted therapeutic possibilities for the treatment of t(8;21) AML that require further study.

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