Hwasun Yang Kang, Miso Jang, Seonyeong Soo Yeon Baek Kim, Jiwon Gyeongun Kim Kim, Dongwoo Ha, Junsu Seung Kim, Jong Jung, Cheulhee Kim, Nam-Jung Cho, Sung-Yup Shin, Woong-Hee Lee, Juyong Ko, Junsu Lee, Ansoo Keum, Gyochang Lee, Sang hee Kang, Taek 2024-02-07T05:11:21Z 2024-02-07T05:11:21Z 2024-01-30 2024-02 0968-0896 https://pubs.kist.re.kr/handle/201004/148519 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. English Pergamon Press Ltd. Discovery of thiophen-2-ylmethylene bis-dimedone derivatives as novel WRN inhibitors for treating cancers with microsatellite instability Article 10.1016/j.bmc.2024.117588 1 Bioorganic & Medicinal Chemistry, v.100 Bioorganic & Medicinal Chemistry 100 N scie scopus 001175410100001 Biochemistry & Molecular Biology Chemistry, Medicinal Chemistry, Organic Biochemistry & Molecular Biology Pharmacology & Pharmacy Chemistry Article EMPIRICAL SCORING FUNCTIONS WERNER SYNDROME HELICASE SYNTHETIC LETHALITY SMALL-MOLECULE SYNDROME PROTEIN DNA-DAMAGE DOCKING Synthetic lethality Korea Microsatellite instability WRN inhibitor Anticancer Thiophene bis-Dimedone