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

Jieyu Xu; Jin Peng; Shu Sun; Donghai Wang; Wei Yuan; Xueying Yang; Ting Shi; Rong Wang; Hudan Liu; Pumin Zhang; Hong-Hu Zhu

doi:10.1111/bjh.19492

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

Br J Haematol. 2024 Apr 29. doi: 10.1111/bjh.19492. Online ahead of print.

Authors

Jieyu Xu^{1

2

3}, Jin Peng⁴, Shu Sun^{1

2}, Donghai Wang^{5

6}, Wei Yuan⁷, Xueying Yang¹, Ting Shi^{1

2

3}, Rong Wang^{1

2

3}, Hudan Liu^{5

6}, Pumin Zhang^{4

8

9}, Hong-Hu Zhu^{1

2

3}

Affiliations

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.

PMID: 38685813
DOI: 10.1111/bjh.19492

Abstract

T-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.

Keywords: CT1113; ICN1; SREBP1; T‐ALL; USP28.

Abstract

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