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Bioorg Med Chem ; 100: 117588, 2024 Feb 15.
Artículo en Inglés | MEDLINE | ID: mdl-38295487

RESUMEN

Microsatellite instability (MSI) is a hypermutable condition caused by DNA mismatch repair system defects, contributing to the development of various cancer types. Recent research has identified Werner syndrome ATP-dependent helicase (WRN) as a promising synthetic lethal target for MSI cancers. Herein, we report the first discovery of thiophen-2-ylmethylene bis-dimedone derivatives as novel WRN inhibitors for MSI cancer therapy. Initial computational analysis and biological evaluation identified a new scaffold for a WRN inhibitor. Subsequent SAR study led to the discovery of a highly potent WRN inhibitor. Furthermore, we demonstrated that the optimal compound induced DNA damage and apoptotic cell death in MSI cancer cells by inhibiting WRN. This study provides a new pharmacophore for WRN inhibitors, emphasizing their therapeutic potential for MSI cancers.


Asunto(s)
Inestabilidad de Microsatélites , Neoplasias , Tiofenos , Humanos , Ciclohexanonas , Neoplasias/tratamiento farmacológico , Neoplasias/genética , Helicasa del Síndrome de Werner/antagonistas & inhibidores , Helicasa del Síndrome de Werner/metabolismo , Tiofenos/química , Tiofenos/farmacología
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