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

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

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: slee19@kist.re.kr.
  • 16 Brain Science Institute, Korea Institute of Science and Technology, Seoul 02792, Republic of Korea. Electronic address: tkang@kist.re.kr.
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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