1. Discovery of novel small molecules targeting the USP21/JAK2/STAT3 axis for the treatment of triple-negative breast cancer.
- Author
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Long L, Xu J, Qi X, Pen Y, Wang C, Jiang W, Peng X, Hu Z, Yi W, Xie L, Lei X, Wang Z, and Zhuo L
- Subjects
- Humans, Structure-Activity Relationship, Cell Proliferation drug effects, Animals, Drug Discovery, Molecular Structure, Small Molecule Libraries chemistry, Small Molecule Libraries pharmacology, Small Molecule Libraries chemical synthesis, Female, Dose-Response Relationship, Drug, Drug Screening Assays, Antitumor, Cell Line, Tumor, Mice, Paclitaxel pharmacology, Paclitaxel chemistry, Triple Negative Breast Neoplasms drug therapy, Triple Negative Breast Neoplasms pathology, Triple Negative Breast Neoplasms metabolism, STAT3 Transcription Factor metabolism, STAT3 Transcription Factor antagonists & inhibitors, Janus Kinase 2 metabolism, Janus Kinase 2 antagonists & inhibitors, Antineoplastic Agents pharmacology, Antineoplastic Agents chemistry, Antineoplastic Agents chemical synthesis, Ubiquitin Thiolesterase antagonists & inhibitors, Ubiquitin Thiolesterase metabolism
- 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., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Masson SAS. All rights reserved.)
- Published
- 2024
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