Abstract
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.
Original language | English |
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Article number | 117588 |
Journal | Bioorganic and Medicinal Chemistry |
Volume | 100 |
DOIs | |
Publication status | Published - 15 Feb 2024 |
Bibliographical note
Publisher Copyright:© 2024 Elsevier Ltd
Keywords
- Anticancer
- Microsatellite instability
- Synthetic lethality
- Thiophene
- WRN inhibitor
- bis-Dimedone