ETX-880：一种潜在的同类最佳、口服、高效且选择性的Werner解旋酶共价抑制剂，用于治疗微卫星高度不稳定（MSI-H）癌症

DNA mismatch repair (dMMR) defects occur in a broad range of cancers and are characterized by genomic instability due to TA repeat expansion, a condition known as microsatellite instability-high (MSI-H). The use of immune checkpoint inhibitors (ICI) in MSI-H cancers has improved patient outcomes, but ~30-40% of patients do not respond and ~20-25% become refractory to ICI. Genetic ablation or pharmacological inhibition of Werner RecQ like, ATP-dependent helicase (WRN) activity has been shown to induce growth arrest and apoptosis in MSI-H cancer cells, but not in microsatellite stable (MSS) cells. Early clinical data with RO7589831 (covalent) and HRO761 (non-covalent) WRN inhibitors demonstrated clinical responses, validating WRN as an actionable target, but uncertainty remains on their ability to fully engage WRN. ETX-880 is a novel, potent and selective small molecule inhibitor of WRN for the treatment of MSI-H cancers. ETX-880 acts through an allosteric, ATP-cooperative binding mechanism and covalent ligation of WRN at cysteine 727 (C727). The preclinical activity of ETX-880 was characterized and compared to clinical stage WRN inhibitors, including RO7589831, HRO761, and GSK4418959 (non-covalent). ETX-880 demonstrated >2-fold tighter binding to WRN than RO7589831 (ETX-880 K I = 0.44 µM versus RO7589831 K I = 1.05 µM) with comparable reactivity for WRN C727. ETX-880 selectively inhibits the ATPase and DNA unwinding activities of WRN with 2-fold greater potency than RO7589831, excellent selectivity against other RecQ helicases, and no activity for the WRN C727A mutant protein. ETX-880 shows strong anti-proliferative effects in a broad panel of MSI-H cancer cell lines with no measurable effects in MSS cells. In MSI-H cancer cells, ETX-880 shows 4-fold more potent anti-proliferative activity than RO7589831 and HRO761 and is ~30-fold more potent than GSK4418959. In vivo , ETX-880 depletes WRN protein and induces DNA damage markers in tumors and leads to deeper and more sustained tumor regressions than RO7589831 in an MSI-H colorectal cancer xenograft model. At the efficacious dose, ETX-880 achieves 100% target occupancy (TO) at 2 hours post dose and maintains ~85% TO at 24 hours, in contrast to RO7589831 which shows substantial loss (~40%) of TO by 24 hours. ETX-880 displays favorable drug-like properties, including good in vitro ADMET, excellent metabolic stability with low in vivo clearance and high oral bioavailability and exposures across animal species. Importantly, human PK predictions reveal low clearance, high oral bioavailability and long half-life, supporting a low once daily oral efficacious dose. Overall, ETX-880 is a potent, selective, covalent WRN inhibitor with excellent ADMET properties leading to deep and sustained target coverage, highlighting its best-in-class potential in MSI-H cancers.