Related Experiment Video
Updated: May 27, 2025
Detection of a Circulating MicroRNA Custom Panel in Patients with Metastatic Colorectal Cancer
Published on: March 14, 2019
Discovery of novel WRN inhibitors for treating MSI-H colorectal cancers
Byul Moon1, Ahra Go2, Seulki Park3
1Aging Convergence Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, 34141, South Korea.
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.
Insights
Researchers explored new WRN inhibitors for microsatellite instability-high (MSI-H) cancers. A novel compound, KWR095, demonstrated significant anti-proliferative effects in preclinical studies, offering potential for MSI-H cancer therapy.
Area of Science:
- Biochemistry
- Genetics
- Oncology
Background:
- The Werner protein (WRN), a RecQ helicase, is crucial for genome maintenance.
- WRN is a synthetic lethal target in microsatellite instability-high (MSI-H) cancers.
- HRO761, a WRN inhibitor, was investigated for MSI-H colorectal cancer (CRC).
Purpose of the Study:
- To develop novel chemical entities targeting WRN by bioisosteric replacement.
- To evaluate new WRN inhibitors for potential MSI-H cancer therapeutics.
Main Methods:
- Bioisosteric replacement of HRO761's hydroxyl pyrimidine residue.
- In vitro ATPase and cell proliferation assays.
- In vivo anti-proliferative studies of synthesized compounds.
Main Results:
- Two novel compounds exhibited comparable or superior efficacy to HRO761 in vitro.
- The synthesized WRN inhibitor KWR095 showed significant anti-proliferative effects in vivo.
- Identified promising candidates for MSI-H cancer treatment.
Conclusions:
- Novel bicyclic structures offer a promising avenue for WRN inhibitor development.
- KWR095 demonstrates potential as a therapeutic agent for MSI-H cancers.
- Further investigation of KWR095 is warranted for clinical application in CRC.
