Preclinical testing of CT1113, a novel USP28 inhibitor, for the treatment of T‐cell acute lymphoblastic leukaemia

Author:

Xu Jieyu123,Peng Jin4,Sun Shu12,Wang Donghai56,Yuan Wei7,Yang Xueying1,Shi Ting123,Wang Rong123,Liu Hudan56,Zhang Pumin489,Zhu Hong‐Hu123ORCID

Affiliation:

1. Department of Hematology, The First Affiliated Hospital Zhejiang University School of Medicine Hangzhou Zhejiang China

2. Zhejiang Provincial Key Laboratory of Hematopoietic Malignancy Zhejiang University Hangzhou Zhejiang China

3. Liangzhu Laboratory Zhejiang University Medical Center Hangzhou Zhejiang China

4. Zhejiang Provincial Key Laboratory of Pancreatic Disease The First Affiliated Hospital of Zhejiang University School of Medicine Hangzhou Zhejiang China

5. Department of Hematology Zhongnan Hospital of Wuhan University, Wuhan University Wuhan China

6. Frontier Science Center for Immunology and Metabolism, Medical Research Institute Wuhan University Wuhan China

7. Department of Hematology Affiliated Hospital of Jiujiang University Jiujiang Jiangxi China

8. Institute of Translational Medicine Zhejiang University Medical School Hangzhou Zhejiang China

9. Cancer Center Zhejiang University Hangzhou Zhejiang China

Abstract

SummaryT‐cell acute lymphoblastic leukaemia (T‐ALL) is a highly aggressive and heterogeneous lymphoid malignancy with poor prognosis in adult patients. Aberrant activation of the NOTCH1 signalling pathway is involved in the pathogenesis of over 60% of T‐ALL cases. Ubiquitin‐specific protease 28 (USP28) is a deubiquitinase known to regulate the stability of NOTCH1. Here, we report that genetic depletion of USP28 or using CT1113, a potent small molecule targeting USP28, can strongly destabilize NOTCH1 and inhibit the growth of T‐ALL cells. Moreover, we show that USP28 also regulates the stability of sterol regulatory element binding protein 1 (SREBP1), which has been reported to mediate increased lipogenesis in tumour cells. As the most critical transcription factor involved in regulating lipogenesis, SREBP1 plays an important role in the metabolism of T‐ALL. Therefore, USP28 may be a potential therapeutic target, and CT1113 may be a promising novel drug for T‐ALL with or without mutant NOTCH1.

Publisher

Wiley

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