A Phenotypic Approach to the Discovery of Potent G-Quadruplex Targeted Drugs

Molecules, Journal Year: 2024, Volume and Issue: 29(15), P. 3653 - 3653

Published: Aug. 1, 2024

G-quadruplex (G4) sequences, which can fold into higher-order G4 structures, are abundant in the human genome and over-represented promoter regions of many genes involved cancer initiation, progression, metastasis. They plausible targets for G4-binding small molecules, would, case G4s, result transcriptional downregulation these genes. However, structural information is currently available on only a very number G4s their ligand complexes. This limitation, coupled with restricted G4-containing most complex cancers, has led to development phenotypic-led approach drug discovery. was illustrated by discovery several generations tri- tetra-substituted naphthalene diimide (ND) ligands that were found show potent growth inhibition pancreatic cell lines active vivo models this hard-to-treat disease. The cycles have culminated highly ND derivative, QN-302, being evaluated Phase 1 clinical trial. major whose expression been down-regulated QN-302 presented here: all contain propensity be up-regulated cancer. Some also upregulated other supporting hypothesis pan-G4 potential utility beyond

Language: Английский

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Deciphering Binding Potential of Naphthalimide–Coumarin Conjugate with c-MYC G-Quadruplex for Developing Anticancer Agents: A Spectroscopic and Molecular Modeling Approach

ACS Applied Bio Materials, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 28, 2025

It has been well accumulated that G-quadruplex (G4-DNA) great anticancer relevance, and various heterocyclic moieties have synthesized examined as potent G4-DNA binders with promising activity. Here, we a series of naphthalimide-triazole-coumarin conjugates by substituting amines further examine their activity against 60 human cancer cell lines at 10 μM. One five dose concentration results reveal low values MG-MID GI50 for compounds including 8a (3.18 μM), 8b (13.11 8e (7.68 μM) 8f (1.75 μM). Further apoptosis manifests all can induce in cells stabilizing the c-MYC promoter G-quadruplex. Therefore, G-quadruplex-mediated pathway may be responsible these naphthalimide-coumarin caused cells. multispectroscopic techniques are employed to evaluate binding molecules where four readily bind stabilize it high constant, leading inhibition Binding studies toward ct-DNA disclose do not interact ds-DNA thus selectively target exert All active greater affinity Human Serum Albumin (HSA) HSA constant 12 × 104 M-1 (8a), 13.0 (8b), 14.2 (8e), 16.3 (8f). Thus, killing derivatives feasibly occur due ability forming promoters unfold agents taken clinical trials.

Language: Английский

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Harnessing G-quadruplex ligands for lung cancer treatment: A comprehensive overview

Drug Discovery Today, Journal Year: 2023, Volume and Issue: 28(12), P. 103808 - 103808

Published: Oct. 29, 2023

Lung cancer (LC) remains a leading cause of mortality worldwide, and new therapeutic strategies are urgently needed. One such approach revolves around the utilization four-stranded nucleic acid secondary structures, known as G-quadruplexes (G4), which formed by G-rich sequences. Ligands that bind selectively to G4 structures present promising strategy for regulating crucial cellular processes involved in progression LC, rendering them potent agents lung treatment. In this review, we offer summary recent advancements development ligands capable targeting specific genes associated with cancer.

Language: Английский

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Design and synthesis of novel structures with anti-tumor effects: Targeting telomere G-quadruplex and hTERT

Bioorganic & Medicinal Chemistry Letters, Journal Year: 2024, Volume and Issue: unknown, P. 130083 - 130083

Published: Dec. 1, 2024

Language: Английский

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Machine learning-based prediction of DNA G-quadruplex folding topology with G4ShapePredictor

Scientific Reports, Journal Year: 2024, Volume and Issue: 14(1)

Published: Oct. 16, 2024

Deoxyribonucleic acid (DNA) is able to form non-canonical four-stranded helical structures with diverse folding patterns known as G-quadruplexes (G4s). G4 topologies are classified based on their relative strand orientation following the 5' 3' phosphate backbone polarity. Broadly, either parallel (4+0), antiparallel (2+2), or hybrid (3+1). G4s play crucial roles in biological processes such DNA repair, replication, transcription and have thus emerged targets drug design. While computational models been developed predict formation, there currently no existing model capable of predicting topology its nucleic sequence. Therefore, we introduce G4ShapePredictor (G4SP), an application featuring a collection multi-classification machine learning that trained custom dataset combining entries from literature in-house circular dichroism experiments. designed accurately potassium (

Language: Английский

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Insight into Stabilization of G‐Quadruplex in c‐MYC Region with Phenanthroimidazoisoindol‐Acrylates and their Binding Behaviour towards Human Serum Albumin

ChemMedChem, Journal Year: 2024, Volume and Issue: unknown

Published: Dec. 16, 2024

The interaction of G-quadruplex (non-canonical DNA) with suitable compounds for their stabilization at the promoter region oncogenes has become a potential anticancer approach. We have studied phenanthroimidazoisoindol-acrylates derivatives c-MYC G-quadruplex. A series 20 were evaluated activity against human cancer cell lines, where 3 fa, ha, and ae shown broad-spectrum activities most lines inactive towards normal lines. Various spectroscopic techniques been used to study these compounds. studies reveal strong binding all three significant selectivity over dsDNA, constant order 10

Language: Английский

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