Design, synthesis, and structure-activity relationship studies of triazolo-pyrimidine derivatives as WRN inhibitors for the treatment of MSI tumors

  • Eur J Med Chem. 2025 Jan 15:282:117039. doi: 10.1016/j.ejmech.2024.117039.
Qibang Sui  1 ,  Yuanyang Zhou  2 ,  Manjia Li  3 ,  Dan Wang  3 ,  Rongrong Cui  4 ,  Xiaoying Cai  5 ,  Jia Liu  3 ,  Xiaofeng Wang  5 ,  Dan Teng  4 ,  Jingyi Zhou  6 ,  Hui Hou  7 ,  Sulin Zhang  8 ,  Mingyue Zheng  9
Affiliations
  • 1. Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China; Key Laboratory of Marine Drugs, Chinese Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao, Shandong, 266003, China.
  • 2. School of Life Science and Technology, ShanghaiTech University, Shanghai, 201210, China; Lingang Laboratory, Shanghai, 200031, China.
  • 3. School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, 210023, China.
  • 4. Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China; University of Chinese Academy of Sciences, Beijing, 100049, China.
  • 5. Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China; University of Chinese Academy of Sciences, Beijing, 100049, China; School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, 310024, China.
  • 6. Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China; Lingang Laboratory, Shanghai, 200031, China; School of Physical Science and Technology, ShanghaiTech University, Shanghai, 201210, China.
  • 7. Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China; Key Laboratory of Marine Drugs, Chinese Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao, Shandong, 266003, China. Electronic address: [email protected].
  • 8. Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China; University of Chinese Academy of Sciences, Beijing, 100049, China. Electronic address: [email protected].
  • 9. Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China; School of Life Science and Technology, ShanghaiTech University, Shanghai, 201210, China; Lingang Laboratory, Shanghai, 200031, China; School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, 210023, China; University of Chinese Academy of Sciences, Beijing, 100049, China; School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, 310024, China. Electronic address: [email protected].
PMID: 39561494 DOI: 10.1016/j.ejmech.2024.117039
Abstract

Werner syndrome RecQ helicase (WRN), a member of the RecQ helicase family, has recently been identified as a synthetic lethal target in microsatellite instability (MSI) tumors. The triazolo-pyrimidine compound HRO761 is the first WRN inhibitor to enter clinical trials, but research on this scaffold remains limited. Here, we designed a series of derivatives to systematically study the structure-activity relationship (SAR) of triazolo-pyrimidine scaffolds, leading to the discovery of compound S35. S35 exhibited excellent WRN helicase inhibitory activity (ADP-Glo kinase assay IC50 = 16.1 nM, fluorometric helicase assay IC50 = 23.5 nM). Additionally, S35 exhibited excellent cellular selectivity, with antiproliferative activity against multiple MSI cell lines (GI50 = 36.4-306 nM), while the GI50 values for multiple microsatellite stability (MSS) cell lines were greater than 20,000 nM. Furthermore, we observed that compound S35 induced DNA damage and caused G2/M cell cycle arrest in MSI cells, which did not occur in MSS cells. S35 demonstrated favorable oral pharmacokinetic properties, with oral administration resulting in dose-dependent tumor growth inhibition in the SW48 xenograft model. These findings provide a promising outlook for the development of WRN inhibitors for the treatment of MSI tumors.

Keywords
MSI tumors; Synthetic lethal; Triazolo-pyrimidine derivatives; WRN inhibitors.
Products