Structural Optimization of CHI3L1 Inhibitors with Improved Pharmacokinetics and Functional Activity in 3D Glioblastoma Models

Chitinase-3-like protein 1 (CHI3L1) is a key driver of glioblastoma (GBM) progression and an emerging therapeutic target. Building on the CHI3L1 inhibitor <b>11g</b> , we optimized the scaffold through medicinal chemistry to assess structure-property relationships and improve pharmacokinetics. Using microscale thermophoresis (MST) and computational studies, we validated <b>10p</b> , which exhibits a CHI31 binding affinity ( <i>K</i> _d ) of 13.22 µM. Notably, <b>10p</b> overcomes previous developability hurdles by achieving a kinetic solubility of 758 µM, a five-fold improvement over <b>11g</b> . It further demonstrates high metabolic stability across species and no hERG inhibition. In 3D GBM spheroid models, <b>10p</b> significantly reduced tumor viability, mass, and migration, exceeding the efficacy of prior analogues. Collectively, these findings establish <b>10p</b> as a potent CHI3L1 inhibitor with a superior pharmacokinetic profile and robust functional activity, marking it as a promising candidate for further GBM drug development.