2. Academic Validation
  3. Discovery of novel small molecules targeting the USP21/JAK2/STAT3 axis for the treatment of triple-negative breast cancer

Discovery of novel small molecules targeting the USP21/JAK2/STAT3 axis for the treatment of triple-negative breast cancer

  • Eur J Med Chem. 2024 May 16:273:116500. doi: 10.1016/j.ejmech.2024.116500.
Lin Long 1,  Jiachi Xu 2,  Xiaowen Qi 3,  Yan Pen 4,  Chengkun Wang 5,  Weifan Jiang 4,  Xue Peng 4,  Zecheng Hu 3,  Wenjun Yi 6,  Liming Xie 7,  Xiaoyong Lei 8,  Zhen Wang 9,  Linsheng Zhuo 10
Affiliations

Affiliations

  • 1 The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, 421001, China; School of Pharmaceutical Science, Hengyang Medical School, University of South China, Hengyang, 421001, China.
  • 2 The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, 421001, China; Department of General Surgery, The Second Xiangya Hospital of Central South University, Changsha, 410011, China.
  • 3 The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, 421001, China.
  • 4 School of Pharmaceutical Science, Hengyang Medical School, University of South China, Hengyang, 421001, China.
  • 5 Hunan Province Key Laboratory of Tumor Cellular & Molecular Pathology, Cancer Research Institute, Hengyang Medical School, University of South China, Hengyang, 421001, China.
  • 6 Department of General Surgery, The Second Xiangya Hospital of Central South University, Changsha, 410011, China.
  • 7 The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, 421001, China. Electronic address: xieliming2019@usc.edu.cn.
  • 8 The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, 421001, China; School of Pharmaceutical Science, Hengyang Medical School, University of South China, Hengyang, 421001, China. Electronic address: leix_yong@163.com.
  • 9 The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, 421001, China; School of Pharmaceutical Science, Hengyang Medical School, University of South China, Hengyang, 421001, China; National Health Commission Key Laboratory of Birth Defect Research and Prevention Hunan Provincial Maternal and Child Health Care Hospital, Changsha, Hunan 410008, China. Electronic address: zhenw@usc.edu.cn.
  • 10 The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, 421001, China; School of Pharmaceutical Science, Hengyang Medical School, University of South China, Hengyang, 421001, China; National Health Commission Key Laboratory of Birth Defect Research and Prevention Hunan Provincial Maternal and Child Health Care Hospital, Changsha, Hunan 410008, China. Electronic address: lszhuo@usc.edu.cn.
PMID: 38776807 DOI: 10.1016/j.ejmech.2024.116500
Abstract

The deficiency in available targeted agents and frequency of chemoresistance are primary challenges in clinical management of triple-negative breast Cancer (TNBC). The aberrant expression of USP21 and JAK2 represents a characterized mechanism of TNBC progression and resistance to paclitaxel (PTX). Despite its clear that high expression of USP21-mediated de-ubiquitination leads to increased levels of JAK2 protein, we lack regulator molecules to dissect the mechanisms that the interaction between USP21 and JAK2 contributes to the phenotype and resistance of TNBC. Here, we report a USP21/JAK2/STAT3 axis-targeting regulator 13c featuring a N-anthraniloyl tryptamine scaffold that showed excellent anti-TNBC potency and promising safety profile. Importantly, the therapeutic potential of using 13c in combination with PTX in PTX-resistant TNBC was demonstrated. This study showcases N-anthraniloyl tryptamine derivatives as a novel anti-TNBC chemotype with a pharmacological mode of action targeting the USP21/JAK2/STAT3 axis and provides a potential therapeutic target for the treatment of TNBC.

Keywords

JAK2; STAT3; Triple-negative breast cancer; USP21; Ubiquitination.

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