Muscone derivative ZM-32 inhibits breast tumor angiogenesis by suppressing HuR-mediated VEGF and MMP9 expression

Biomed Pharmacother. 2021 Apr:136:111265. doi: 10.1016/j.biopha.2021.111265.

Liu-Qing Yang ¹, Shao-Peng Yu ¹, Yan-Tao Yang ², Yi-Shuang Zhao ³, Fei-Yun Wang ¹, Yao Chen ¹, Qing-Hua Li ¹, Ping Tian ⁴, Yu-Ying Zhu ⁵, Jian-Ge Zhang ⁶, Guo-Qiang Lin ⁷

Affiliations

1 The Research Center of Chiral Drugs, Innovation Research Institute of Traditional Chinese Medicine (IRI), Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China.
2 Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450000, China.
3 CAS Key Laboratory of Synthetic Chemistry of Natural Substances, Center for Excellence in Molecular Synthesis, Shanghai Institute of Organic Chemistry, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, 200032, China.
4 The Research Center of Chiral Drugs, Innovation Research Institute of Traditional Chinese Medicine (IRI), Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China. Electronic address: tianping@shutcm.edu.cn.
5 The Research Center of Chiral Drugs, Innovation Research Institute of Traditional Chinese Medicine (IRI), Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China. Electronic address: ying.yu.zhu@163.com.
6 The Research Center of Chiral Drugs, Innovation Research Institute of Traditional Chinese Medicine (IRI), Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China. Electronic address: jgzhang@shutcm.edu.cn.
7 The Research Center of Chiral Drugs, Innovation Research Institute of Traditional Chinese Medicine (IRI), Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China; CAS Key Laboratory of Synthetic Chemistry of Natural Substances, Center for Excellence in Molecular Synthesis, Shanghai Institute of Organic Chemistry, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, 200032, China.

PMID: 33450490 DOI: 10.1016/j.biopha.2021.111265

Abstract

Inhibition of tumor angiogenesis is a highly effective strategy for Cancer treatment. Human antigen R (HuR), an RNA-binding protein, is overexpressed in many cancers and regulates the mRNAs of multiple angiogenic factors by binding to the adenylate-uridylate-rich element in their 3' untranslated region. HuR protein has been demonstrated to be an important regulatory factor in macrophage-mediated angiogenesis, a process in which macrophages are critical for tumor progression. Muscone is a synthetic equivalent of musk, and recent studies have shown that it has a regulatory effect on angiogenesis. In this study, we synthesized five series of muscone derivatives and discovered that compound ZM-32 was effective in preventing HuR RRM1/2-Vegf-a mRNA complex formation. ZM-32 bound to HuR RRM1/2 protein with a K_D value of 521.7 nmol/L. Furthermore, ZM-32 inhibited endothelial cell proliferation, migration, and tubule formation, and suppressed the VEGF/VEGFR2/KDR/Flk-1/ERK1/2 signaling axis mediated by macrophages in vitro. We also demonstrated that ZM-32 effectively prevented the proliferation and migration of breast Cancer cells and inhibited the growth and angiogenesis of MDA-MB-231 xenograft tumors without any obvious toxicity in vivo. Mechanistically, exposure to ZM-32 influenced the mRNA stability of VEGF-A and Mmp9 in a HuR-dependent manner in both macrophages and MDA-MB-231 cells. Thus, in this study we identified a new muscone derivative, ZM-32, with anti-angiogenesis effects mediated via targeting HuR in breast Cancer, that may become a potentially valuable lead compound for anti-cancer angiogenesis.

Keywords

Angiogenesis; Breast cancer; HuR; Macrophage; Muscone derivatives.

Products

Cat. No.

Product Name

Description

Target

Research Area
HY-163760

ZM-32

HuR Inhibitor

HuR; MMP

Cancer

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