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

  • Bioorg Med Chem. 2024 Feb 15:100:117588. doi: 10.1016/j.bmc.2024.117588.
Hwasun Yang  1 ,  Miso Kang  2 ,  Seonyeong Jang  3 ,  Soo Yeon Baek  4 ,  Jiwon Kim  5 ,  Gyeong Un Kim  6 ,  Dongwoo Kim  7 ,  Junsu Ha  8 ,  Jong Seung Kim  9 ,  Cheulhee Jung  10 ,  Nam-Jung Kim  11 ,  Sung-Yup Cho  12 ,  Woong-Hee Shin  13 ,  Juyong Lee  14 ,  Junsu Ko  8 ,  Ansoo Lee  6 ,  Gyochang Keum  6 ,  Sanghee Lee  15 ,  Taek Kang  16
Affiliations
  • 1. Brain Science Institute, Korea Institute of Science and Technology, Seoul 02792, Republic of Korea; Department of Chemistry, Korea University, Seoul 02841, Republic of Korea.
  • 2. Brain Science Institute, Korea Institute of Science and Technology, Seoul 02792, Republic of Korea; Department of Fundamental Pharmaceutical Sciences, Graduate School, Kyung Hee University, Seoul 02447, Republic of Korea.
  • 3. Brain Science Institute, Korea Institute of Science and Technology, Seoul 02792, Republic of Korea; Department of Biotechnology, College of Life Sciences and Biotechnology, Korea University, Seoul 02841, Republic of Korea.
  • 4. Brain Science Institute, Korea Institute of Science and Technology, Seoul 02792, Republic of Korea.
  • 5. Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul 03080, Republic of Korea.
  • 6. Brain Science Institute, Korea Institute of Science and Technology, Seoul 02792, Republic of Korea; Division of Bio-Medical Science & Technology, KIST School, University of Science and Technology, Seoul 02792, Republic of Korea.
  • 7. College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea.
  • 8. Arontier Co., Ltd., Seoul 06735, Republic of Korea.
  • 9. Department of Chemistry, Korea University, Seoul 02841, Republic of Korea.
  • 10. Department of Biotechnology, College of Life Sciences and Biotechnology, Korea University, Seoul 02841, Republic of Korea.
  • 11. Department of Fundamental Pharmaceutical Sciences, Graduate School, Kyung Hee University, Seoul 02447, Republic of Korea.
  • 12. Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul 03080, Republic of Korea; Medical Research Center, Genomic Medicine Institute, Seoul National University College of Medicine, Seoul 03080, Republic of Korea; Cancer Research Institute, Seoul National University, Seoul 03080, Republic of Korea.
  • 13. Arontier Co., Ltd., Seoul 06735, Republic of Korea; Department of Medicine, Korea University College of Medicine, Seoul 02708, Republic of Korea.
  • 14. Arontier Co., Ltd., Seoul 06735, Republic of Korea; Research Institute of Pharmaceutical Science, Seoul National University, Seoul 08826, Republic of Korea; Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, Seoul National University, Seoul 08826, Republic of Korea.
  • 15. Brain Science Institute, Korea Institute of Science and Technology, Seoul 02792, Republic of Korea; Department for HY-KIST Bio-convergence, Hanyang University, Seoul 04763, Republic of Korea. Electronic address: [email protected].
  • 16. Brain Science Institute, Korea Institute of Science and Technology, Seoul 02792, Republic of Korea. Electronic address: [email protected].
PMID: 38295487 DOI: 10.1016/j.bmc.2024.117588
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.

Keywords
Anticancer; Microsatellite instability; Synthetic lethality; Thiophene; WRN inhibitor; bis-Dimedone.
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