Cited by 101DNA and Nucleic Acid ChemistryMetal complexes synthesis and propertiesSupramolecular Chemistry and Complexes

Discovery of a New Four-Leaf Clover-Like Ligand as a Potent c-MYC Transcription Inhibitor Specifically Targeting the Promoter G-Quadruplex

Hu, Ming-Hao, Wang, Yu-Qing, Yu, Ze-Yi, Hu, Lu-Ni, Ou, Tian-Miao, Chen, Shuo-Bin, Huang, Zhi-Shu, Tan, Jia-Heng·2018·Journal of Medicinal Chemistry

Abstract

Downregulating transcription of the oncogene c-MYC is a feasible strategy for cancer therapy. Stabilization of the G-quadruplex structure present in the c-MYC promoter can suppress c-MYC transcription. Thus, far, several ligands targeting this structure have been developed. However, most have shown no selectivity for the c-MYC G-quadruplex over other G-quadruplexes, leading to uncertain side effects. In this study, through structural modification of aryl-substituted imidazole/carbazole conjugates, a brand-new, four-leaf clover-like ligand called IZCZ-3 was found to preferentially bind and stabilize the c-MYC G-quadruplex. Further intracellular studies indicated that IZCZ-3 provoked cell cycle arrest and apoptosis and thus inhibited cell growth, primarily by blocking c-MYC transcription through specific targeting of the promoter G-quadruplex structure. Notably, IZCZ-3 effectively suppressed tumor growth in a mouse xenograft model. Accordingly, this work provides an encouraging example of a selective small molecule that can target one particular G-quadruplex structure, and the selective ligand might serve as an excellent anticancer agent.

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Crossref · 10.1021/acs.jmedchem.7b01697

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Authors
Hu, M.-H., Wang, Y.-Q., Yu, Z.-Y., Hu, L.-N., Ou, T.-M., Chen, S.-B., Huang, Z.-S., & Tan, J.-H.
Affiliations
  • Sun Yat-sen University (CN)
  • School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou 510006, China
Corresponding author
  • Chen, Shuo-Bin
  • Tan, Jia-Heng
Venue
Journal of Medicinal Chemistry
Published
2018-02-23
Volume
61
Issue
6
Pages
2447-2459
ISSN
  • 0022-2623 (ISSN-L)
  • 1520-4804
OpenAlex
W2788513881
Cited by
101
References
46
Citations by year
2026: 6 · 2025: 6 · 2024: 11 · 2023: 10 · 2022: 13 · 2021: 18 · 2020: 18 · 2019: 12 · 2018: 7
FWCI
4.89
Type
journal article
Language
en
Open access
closed
Locations
  • Journal of Medicinal Chemistry (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • State Administration of Foreign Experts Affairs (B16047)
  • Ministry of Education of the People's Republic of China (B16047)
  • National Natural Science Foundation of China (21672268, 81330077)
  • Natural Science Foundation of Guangdong Province (2015A030306004, 2017A030308003)
  • Guangdong Provincial Key Laboratory of Construction Foundation (2011A060901014)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA and Nucleic Acid Chemistry
  • Health Sciences › Medicine › Oncology › Metal complexes synthesis and properties
  • Physical Sciences › Chemistry › Organic Chemistry › Supramolecular Chemistry and Complexes
Keywords
c-Myc, G-quadruplex, c-myc promoter, transcriptional inhibition, small-molecule ligands, G-quadruplex stabilization, cell cycle arrest, apoptosis, anticancer agents, tumor growth inhibition
MeSH terms
Animals, Antineoplastic Agents, Carbazoles, Carcinoma, Squamous Cell, Cell Division, Uterine Cervical Neoplasms, Drug Screening Assays, Antitumor, Female, Humans, Imidazoles, Ligands, Mice, Inbred BALB C, Models, Molecular, Promoter Regions, Genetic, Tumor Stem Cell Assay, Proto-Oncogene Proteins c-myc, Xenograft Model Antitumor Assays, Cell Line, Tumor, Mice, G-Quadruplexes, Drug Discovery, Cell Cycle Checkpoints

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