Werner Syndrome RecQ Helicase-IN-1

Werner syndrome RecQ helicase-IN-1 is an inhibitor of the DNA helicase Werner syndrome protein (WRN; IC₅₀ = 100 nM in an enzyme activity assay).¹ It selectively inhibits WRN over the DNA helicases Bloom syndrome protein (BLM), RecQ1, and RecQ5 (IC₅₀s = >100 µM for all in enzyme activity assays) and the growth of SW480 colorectal cancer cells with unstable microsatellites over CAL-33 tongue squamous cell carcinoma cells with stable microsatellites (GI₅₀s = 0.04 and >10 μM, respectively). Werner syndrome RecQ helicase-IN-1 (0.75-10 µM) induces proteosomal degradation of WRN in RKO colon cancer cells. It induces cell cycle arrest at the G₂ phase in HCT116 colorectal cancer cells when used at a concentration of 10 µM. Werner syndrome RecQ helicase-IN-1 (1 or 5 µM) increases the levels of γ histone H2AX (γH2AX) and p21 and the levels of phosphorylated ataxia-telangiectasia and Rad3-related protein/kinase (ATR), checkpoint kinase 2 (Chk2), and ataxia mutated kinase (ATM), markers of DNA damage, in HCT116 and LS411N colorectal cancer cells. In vivo, Werner syndrome RecQ helicase-IN-1 (40, 60, or 120 mg/kg per day) decreases tumor volume without reducing body weight in an SW480 mouse xenograft model.

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1. Ferretti, S., Hamon, J., de Kanter, R., et al. Discovery of WRN inhibitor HRO761 with synthetic lethality in MSI cancers. Nature 629(8011), 443-449 (2024).