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  3. Targeting G-rich sequence to regulate the transcription of murine double minute (MDM) genes in triple-negative breast cancers

Targeting G-rich sequence to regulate the transcription of murine double minute (MDM) genes in triple-negative breast cancers

  • Eur J Med Chem. 2024 Mar 5:267:116156. doi: 10.1016/j.ejmech.2024.116156.
Yuxin Feng 1,  Xuan Xuan 1,  Yuemiao Hu 1,  Jiaguo Lu 1,  Zhiwen Dong 1,  Ziqiang Sun 2,  Hongying Yao 1,  Lei Hu 3,  Qikun Yin 4,  Yi Liu 2,  Hongbo Wang 1
Affiliations

Affiliations

  • 1 School of Pharmacy, Key Laboratory of Molecular Pharmacology and Drug Evaluation (Yantai University), Ministry of Education, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Yantai University, Yantai, 264005, China.
  • 2 School of Chemistry and Chemical Engineering, Yantai University, Yantai, 264005, China.
  • 3 School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China.
  • 4 School of Pharmacy, Key Laboratory of Molecular Pharmacology and Drug Evaluation (Yantai University), Ministry of Education, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Yantai University, Yantai, 264005, China. Electronic address: qkyin@ytu.edu.cn.
PMID: 38295687 DOI: 10.1016/j.ejmech.2024.116156
Abstract

Murine double minute 2 (MDM2) and homologous protein murine double minute X (MDMX) are p53 negative regulators that perform significant driving effects in tumorigenesis, and targeting these oncoproteins has became an efficient strategy in treating cancers. However, the definite antitumor activity and significance ordering of each protein in MDM family is still unclear due to the similar structure and complicated regulation. Herein, we identified two G-rich sequences (G1 and G5) located in the promoter that could assemble the G-quadruplex to respectively inhibit and promote the transcription of the MDM2 and MDMX. Based on this target, we designed and synthesized a novel G-quadruplex ligand A3f and achieved the differentiated regulation of MDM protein. In triple-negative breast Cancer (TNBC) cells, A3f could induce MDM2-dependent proliferation arrest and exhibit additive therapeutic effect with MDMX inhibitors. Overall, this study provided a novel strategy to regulate the transcription of MDM genes by targeting certain G-rich sequences, and discovered an active antitumor molecule for use in TNBC treatment.

Keywords

G-quadruplex; MDM2; MDMX; TNBC treatment; Transcription regulation.

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