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

Qibang Sui; Yuanyang Zhou; Manjia Li; Dan Wang; Rongrong Cui; Xiaoying Cai; Jia Liu; Xiaofeng Wang; Dan Teng; Jingyi Zhou; Hui Hou; Sulin Zhang; Mingyue Zheng

doi:10.1016/j.ejmech.2024.117039

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. Epub 2024 Nov 12.

Authors

Qibang Sui¹, Yuanyang Zhou², Manjia Li³, Dan Wang³, Rongrong Cui⁴, Xiaoying Cai⁵, Jia Liu³, Xiaofeng Wang⁵, Dan Teng⁴, Jingyi Zhou⁶, Hui Hou⁷, Sulin Zhang⁸, Mingyue Zheng⁹

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: houhuisdu@163.com.
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: slzhang@simm.ac.cn.
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: myzheng@simm.ac.cn.

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.

MeSH terms

Animals
Antineoplastic Agents* / chemical synthesis
Antineoplastic Agents* / chemistry
Antineoplastic Agents* / pharmacology
Cell Line, Tumor
Cell Proliferation* / drug effects
Dose-Response Relationship, Drug
Drug Design*
Drug Screening Assays, Antitumor*
Enzyme Inhibitors / chemical synthesis
Enzyme Inhibitors / chemistry
Enzyme Inhibitors / pharmacology
Humans
Mice
Microsatellite Instability / drug effects
Molecular Structure
Pyrimidines* / chemical synthesis
Pyrimidines* / chemistry
Pyrimidines* / pharmacology
Structure-Activity Relationship
Triazoles* / chemical synthesis
Triazoles* / chemistry
Triazoles* / pharmacology
Werner Syndrome Helicase* / antagonists & inhibitors
Werner Syndrome Helicase* / metabolism

Substances

Pyrimidines
Werner Syndrome Helicase
Antineoplastic Agents
Triazoles
WRN protein, human
Enzyme Inhibitors