2. Academic Validation
  3. Discovery of novel WRN inhibitors for treating MSI-H colorectal cancers

Discovery of novel WRN inhibitors for treating MSI-H colorectal cancers

  • Bioorg Med Chem Lett. 2025 Feb 15:120:130141. doi: 10.1016/j.bmcl.2025.130141.
Byul Moon 1,  Ahra Go 2,  Seulki Park 3,  Hyun Jin Kim 4,  Dongju An 5,  Jaehoon Kim 5,  Joo-Youn Lee 2,  Jeong-Hoon Kim 6,  Jong Yeon Hwang 7,  Jung-Ae Kim 8
Affiliations

Affiliations

  • 1 Aging Convergence Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, 34141, South Korea.
  • 2 Therapeutics and Biotechnology Division, Korea Research Institute of Chemical Technology, Daejeon 34114, Republic of Korea.
  • 3 DiseaseTarget Structure Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon 34141, South Korea.
  • 4 Therapeutics and Biotechnology Division, Korea Research Institute of Chemical Technology, Daejeon 34114, Republic of Korea; Medicinal Chemistry and Pharmacology, Korea University of Science and Technology, Daejeon 34113, Republic of Korea.
  • 5 Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Daejeon 34141, South Korea.
  • 6 DiseaseTarget Structure Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon 34141, South Korea; KRIBB School of Bioscience, Korea University of Science and Technology (UST), Daejeon 34113, South Korea. Electronic address: jhoonkim@kribb.re.kr.
  • 7 Therapeutics and Biotechnology Division, Korea Research Institute of Chemical Technology, Daejeon 34114, Republic of Korea; Medicinal Chemistry and Pharmacology, Korea University of Science and Technology, Daejeon 34113, Republic of Korea. Electronic address: jyhwang@krict.re.kr.
  • 8 Aging Convergence Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, 34141, South Korea; KRIBB School of Bioscience, Korea University of Science and Technology (UST), Daejeon 34113, South Korea. Electronic address: jungaekim@kribb.re.kr.
PMID: 39956276 DOI: 10.1016/j.bmcl.2025.130141
Abstract

The Werner protein, WRN, is a member of the RecQ helicase family implicated in genome maintenance. Several large-scale functional genomics screens have identified WRN as a synthetic lethal target in Cancer cell lines with microsatellite instability-high (MSI-H). Accordingly, WRN is considered a potential therapeutic target in MSI-H cancers. HRO761, a non-covalent WRN inhibitor developed by Novartis, entered clinical trial for patients with MSI-H colorectal Cancer (CRC). In this study, we investigated bioisosteric replacement of the hydroxyl pyrimidine residue of HRO761 with several bicyclic structures to obtain a novel chemical entity. In vitro ATPase and cell proliferation assays revealed two candidate chemicals that showed similar or better effects than HRO761. Additionally, an in vivo study demonstrated that KWR095, a newly synthesized WRN inhibitor, has significant anti-proliferative effects compared with vehicle.

Keywords

Colorectal cancer; HRO761; MSI-H; WRN; WRN inhibitor.

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