Discovery of a New Four-Leaf Clover-Like Ligand as a Potent c-MYC Transcription Inhibitor Specifically Targeting the Promoter G-Quadruplex
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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IZCZ-3 inhibits cell growth by inducing cell cycle arrest and apoptosis, and suppresses tumor growth in a mouse xenograft model.
“IZCZ-3 inhibits cell growth by inducing cell cycle arrest and apoptosis, and suppresses tumor growth in a mouse xenograft model, providing a promising avenue for drug”
From Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials (2023) · cites this paper as [585]
Chen and Tan's group reported IZCZ-3, which binds and stabilizes the c-Myc G4 at the molecular level.
“In the same year, Chen and Tan’s group reported a novel four-leaf clover-like ligand, called IZCZ-3 (250), through structural modification of aryl-substituted imidazole/carbazole conjugates, which binds and stabilizes the c-Myc G4 at the molecular level.”
From Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials (2023) · cites this paper as [585]
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Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials
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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
- Publisher
- American Chemical Society (ACS)
- 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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