Structure-Guided Discovery of CHI3L1 Inhibitors from Ultralarge Chemical Spaces for Glioblastoma Therapy.

Glioblastoma (GBM) is a lethal brain tumor with few therapies. Targeting Chitinase 3-like 1 (CHI3L1), we used our SpaceDock structure-based virtual screen of 377 billion compounds, synthesized 60 top hits, and validated nine binders. Lead compound 9e (K d = 19.11 μM) reduced viability and STAT3 signaling in 3D GBM spheroids. These findings demonstrate the potential of reactivity-aware ultralarge screening to identify modulators of nonenzymatic, dynamic targets in complex cancer models.