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

Molecules, Год журнала: 2024, Номер 29(15), С. 3653 - 3653

Опубликована: Авг. 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

Язык: Английский

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Expanding the Functions of KHSRP Protein: Insights into DNA G‐Quadruplex Binding

Advanced Science, Год журнала: 2025, Номер unknown

Опубликована: Янв. 6, 2025

KHSRP (KH-type splicing regulatory protein) is a multifunctional nucleic acid-binding protein that regulates various cellular processes, with critical roles in controlling gene expression. G-quadruplexes (G4s) are noncanonical acid structures involved essential activities, including expression, and recognized as potential therapeutic targets cancer. The biological functions of G4s mediated by proteins making their formation highly dynamic within cells. Therefore, the recognition specific crucial for modulating physiological pathological pathways. Given growing interest DNA G4s, deeper understanding interact them molecular imperative. This study demonstrates binds to these structures. Biophysical analyses provide insights into thermodynamics, kinetics, structural aspects interactions, showing G4 variability significantly influences binding, which KH3 domain plays key role. Validation interactions cancer cells further highlights relevance. Notably, ligand pyridostatin affects KHSRP/G4 both vitro cells, suggesting small molecules can modulate this recognition. These findings underscore KHSRP's role regulating mechanisms through binding G4-forming DNA, positioning it possible target

Язык: Английский

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Design, Synthesis, and Anticancer Activity of Drug-like Iron Chelators/G-Quadruplex Binders as Synergic Dual Targeting Agents

Journal of Medicinal Chemistry, Год журнала: 2025, Номер unknown

Опубликована: Янв. 1, 2025

Iron homeostasis is strictly related to numerous physiological pathways including cell cycle progression and growth. The newest anticancer strategies focus on either depleting the cells with a suitable chelator or increasing their loading by administering iron complexes induce ferroptosis. depletion inhibits proliferation, while overload induces damage of guanine nucleobases in G-quadruplex structures via ROS generation, leading genome instability. Here, we demonstrated that designing molecular chimera embodying structural requirements for both chelation binding can result dual-targeting compounds endowed synergistic effects. We designed, synthesized, tested library such through biophysical biological experiments. Compound

Язык: Английский

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Repurposing FDA-approved drugs to target G-quadruplexes in breast cancer

European Journal of Medicinal Chemistry, Год журнала: 2025, Номер 285, С. 117245 - 117245

Опубликована: Янв. 5, 2025

Язык: Английский

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Recent advances in DNA nanotechnology for cancer detection and therapy: A review

International Journal of Biological Macromolecules, Год журнала: 2025, Номер unknown, С. 142136 - 142136

Опубликована: Март 1, 2025

Язык: Английский

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Anticancer drugs: where are we now?

Expert Opinion on Therapeutic Patents, Год журнала: 2024, Номер 34(7), С. 525 - 527

Опубликована: Май 9, 2024

Язык: Английский

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Chromatin Immunoprecipitation Reveals p53 Binding to G-Quadruplex DNA Sequences in Myeloid Leukemia Cell Lines

ACS Bio & Med Chem Au, Год журнала: 2025, Номер unknown

Опубликована: Фев. 12, 2025

Язык: Английский

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Unlocking the potential of protein-derived peptides to target G-quadruplex DNA: from recognition to anticancer activity

Nucleic Acids Research, Год журнала: 2024, Номер 52(12), С. 6748 - 6762

Опубликована: Июнь 3, 2024

Abstract Noncanonical nucleic acid structures, particularly G-quadruplexes, have garnered significant attention as potential therapeutic targets in cancer treatment. Here, the recognition of G-quadruplex DNA by peptides derived from Rap1 protein is explored, with aim developing novel peptide-based ligands enhanced selectivity and anticancer activity. Biophysical techniques were employed to assess interaction a peptide G-quadruplex-binding domain various biologically relevant structures. Through alanine scanning mutagenesis, key amino acids crucial for identified, leading discovery two improved properties. However, despite their vitro efficacy, these showed limited cell penetration To overcome this challenge, cell-penetrating (CPP)-conjugated derivatives designed, some which exhibited cytotoxic effects on cells. Interestingly, selected CPP-conjugated exerted potent activity across tumour types via G-quadruplex-dependent mechanism. These findings underscore therapy pave way development strategies targeting

Язык: Английский

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G-Quadruplex Forming DNA Sequence Context Is Enriched around Points of Somatic Mutations in a Subset of Multiple Myeloma Patients

International Journal of Molecular Sciences, Год журнала: 2024, Номер 25(10), С. 5269 - 5269

Опубликована: Май 12, 2024

Multiple myeloma (MM) is the second most common hematological malignancy, which remains incurable despite recent advances in treatment strategies. Like other forms of cancer, MM characterized by genomic instability, caused defects DNA repair. Along with mutations repair genes and genotoxic drugs used to treat MM, non-canonical secondary structures (four-stranded G-quadruplex structures) can affect accumulation somatic chromosomal abnormalities tumor cells patients. Here, we tested hypothesis that may influence distribution We sequenced exomes normal 11 patients analyzed data for presence G4 context around points mutations. To identify molecular mechanisms could mutational profile tumors, also signatures as well germline specific SNPs or regulating unwinding. In several patients, found sites are frequently located regions context. This pattern correlated variants these discuss possible implications mutation specificity propose extent enrichment be a novel metric characterizing processes tumors.

Язык: Английский

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Development of a multi-targeted chemotherapeutic approach based on G-quadruplex stabilisation and carbonic anhydrase inhibition

Journal of Enzyme Inhibition and Medicinal Chemistry, Год журнала: 2024, Номер 39(1)

Опубликована: Июнь 18, 2024

A novel class of compounds designed to hit two anti-tumour targets, G-quadruplex structures and human carbonic anhydrases (hCAs) IX XII is proposed. The induction/stabilisation by small molecules has emerged as an anticancer strategy, disrupting telomere maintenance reducing oncogene expression. hCAs are well-established upregulated in many hypoxic tumours contributing metastasis. ligands reported feature a berberine stabiliser scaffold connected moiety inhibiting XII. In vitro experiments showed that our selectively stabilise inhibit crystal structure telomeric complex with one these was obtained, shedding light on the ligand/target interaction mode. most promising significant cytotoxicity against CA IX-positive HeLa cancer cells hypoxia, ability G-quadruplexes within tumour cells.

Язык: Английский

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