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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Pancreatic Tumour Microenvironment and Microenvironment Targeted Therapeutic Approaches

IntechOpen eBooks, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 28, 2025

Pancreatic cancer is characterised by high metastatic potential and poor survival rates. The major reason for this the failure of therapeutic agent to reach target cells due dense desmoplastic microenvironment formed in pancreatic tumours. development an immunosuppressive tumour microenvironment, disruption matrix morphology, reduces success rate immunotherapy, chemotherapy targeted therapy methods used treatment Adenoductal Carcinoma (PDAC). In chapter, components microenvironment; cells, stromal (mesenchymal stem fibroblasts, cancer-associated stellate cells), immune system extracellular (ECM, cytokines, growth factors, DNA small RNAs) are explained. This stroma a vital dynamic structure that regulates growth, metabolism, vascularisation, drug resistance, tolerance metastasis pathways. To comprehend manage intense stroma, it crucial elucidate behaviour cancer. PDAC, most frequent type cancer, microenvironment-targeted approaches then presented as vitro, vivo clinical phase studies.

Language: Английский

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Dissecting macrophage heterogeneity and kaempferol in lung adenocarcinoma: a single-cell transcriptomic approach and network pharmacology

Discover Oncology, Journal Year: 2025, Volume and Issue: 16(1)

Published: Jan. 30, 2025

Lung adenocarcinoma (LUAD) is a leading form of non-small cell lung cancer characterized by complex tumor microenvironment (TME) that influences disease progression and therapeutic response. Tumor-associated macrophages (TAMs) within the TME promote tumorigenesis evasion immune surveillance, though their heterogeneity poses challenges in understanding roles targeting. Additionally, traditional Chinese medicine (TCM) offers potential anti-cancer agents could modulate landscape. We conducted single-cell RNA sequencing (scRNA-seq) on LUAD samples, performing an in-depth analysis macrophage populations expression signatures. Network pharmacology was used to identify TCM components with TAM-modulatory effects, focusing Astragalus membranaceus. Pseudotime trajectory analysis, immunofluorescence staining, vitro assays examined functional TAMs effects selected compounds polarization. Our scRNA-seq identified notable among macrophages, revealing predominant M2-like phenotypes TAMs. highlighted active ingredients, including quercetin, isorhamnetin, kaempferol, targeting genes related function. Survival implicated AHSA1, CYP1B1, SPP1, STAT1 as prognostically significant factors. Further experiments demonstrated kaempferol's efficacy inhibiting M2 polarization, underlining selective influence TAM functionality. This study delineates diverse landscape suggests pivotal role for TAM-mediated immunosuppression. Kaempferol, from TCM, emerges influential agent capable altering potentially enhancing anti-tumoral immunity. These findings underscore translational integrating TCM-derived into immunotherapeutic strategies LUAD.

Language: Английский

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Current status and future directions of small-molecule quadruplex therapeutics in human cancer: Roadmap 2024

Annual reports in medicinal chemistry, Journal Year: 2024, Volume and Issue: unknown, P. 269 - 283

Published: Jan. 1, 2024

Language: Английский

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