Tricyclic and Novel Chemotypes as Selective WRN Helicase Inhibitors for MSI‑H Cancer Therapy

Recent advances targeting WRN helicase highlight a promising synthetic lethality approach for treating microsatellite instability-high (MSI-H) cancers. GlaxoSmithKline and Moma Therapeutics independently developed small molecule inhibitors with distinct chemotypes that disrupt WRN function. Their complementary efforts showcase differentiated selectivity, strategic molecular designs, and a shared focus on exploiting WRN dependency in DNA mismatch repair-deficient tumors.