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
癌细胞
DNA损伤
药效团
程序性细胞死亡
DNA
遗传学
细胞凋亡
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,Seonyeong Jang,Soo Yeon Baek,Jiwon Kim,Gyeong Un Kim,Dongwoo Kim,Junsu 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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