Discovery of thiophen-2-ylmethylene bis-dimedone derivatives as novel WRN inhibitors for treating cancers with microsatellite instability.

Bioorganic & medicinal chemistry 2024 Feb 15

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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. Copyright © 2024 Elsevier Ltd. All rights reserved.

Citation

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. Discovery of thiophen-2-ylmethylene bis-dimedone derivatives as novel WRN inhibitors for treating cancers with microsatellite instability. Bioorganic & medicinal chemistry. 2024 Feb 15;100:117588