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

Lin Long; Jiachi Xu; Xiaowen Qi; Yan Pen; Chengkun Wang; Weifan Jiang; Xue Peng; Zecheng Hu; Wenjun Yi; Liming Xie; Xiaoyong Lei; Zhen Wang; Linsheng Zhuo

doi:10.1016/j.ejmech.2024.116500

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

Eur J Med Chem. 2024 Jul 5:273:116500. doi: 10.1016/j.ejmech.2024.116500. Epub 2024 May 16.

Authors

Lin Long¹, Jiachi Xu², Xiaowen Qi³, Yan Pen⁴, Chengkun Wang⁵, Weifan Jiang⁴, Xue Peng⁴, Zecheng Hu³, Wenjun Yi⁶, Liming Xie⁷, Xiaoyong Lei⁸, Zhen Wang⁹, Linsheng Zhuo¹⁰

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: [email protected].
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: [email protected].
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: [email protected].
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: [email protected].

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.

MeSH terms

Animals
Antineoplastic Agents* / chemical synthesis
Antineoplastic Agents* / chemistry
Antineoplastic Agents* / pharmacology
Cell Line, Tumor
Cell Proliferation / drug effects
Dose-Response Relationship, Drug
Drug Discovery
Drug Screening Assays, Antitumor
Female
Humans
Janus Kinase 2* / antagonists & inhibitors
Janus Kinase 2* / metabolism
Mice
Molecular Structure
Paclitaxel / chemistry
Paclitaxel / pharmacology
STAT3 Transcription Factor* / antagonists & inhibitors
STAT3 Transcription Factor* / metabolism
Small Molecule Libraries / chemical synthesis
Small Molecule Libraries / chemistry
Small Molecule Libraries / pharmacology
Structure-Activity Relationship
Triple Negative Breast Neoplasms* / drug therapy
Triple Negative Breast Neoplasms* / metabolism
Triple Negative Breast Neoplasms* / pathology
Ubiquitin Thiolesterase* / antagonists & inhibitors
Ubiquitin Thiolesterase* / metabolism

Substances

STAT3 Transcription Factor
Janus Kinase 2
STAT3 protein, human
Antineoplastic Agents
JAK2 protein, human
Ubiquitin Thiolesterase
Small Molecule Libraries
Paclitaxel