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  2. 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.
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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