微卫星不稳定性
基因组不稳定性
解旋酶
癌症
化学
癌症研究
DNA修复
DNA损伤
药效团
DNA
遗传学
计算生物学
生物
生物化学
微卫星
基因
核糖核酸
等位基因
作者
Hwasun Yang,Miso Kang,Su-Bum Jang,Soo Yeon Baek,Jihye Kim,Gyeong Un Kim,Dongwoo Kim,Jae Du Ha,Jong Seung Kim,Cheulhee Jung,Nam‐Jung Kim,Sung-Yup Cho,Woong‐Hee Shin,Juyong Lee,Junsu Ko,Ansoo Lee,Gyochang Keum,Sanghee Lee,Taek Kang
标识
DOI:10.1016/j.bmc.2024.117588
摘要
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.
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