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bioRxiv · 10.64898/2026.01.28.702243

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

Kaur, B.·Nada, H.·Gabr, M.
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Abstract

Chitinase-3-like protein 1 (CHI3L1) is a key driver of glioblastoma (GBM) progression and an emerging therapeutic target. Building on the CHI3L1 inhibitor 11g, we optimized the scaffold through medicinal chemistry to assess structure-property relationships and improve pharmacokinetics. Using microscale thermophoresis (MST) and computational studies, we validated 10p, which exhibits a CHI31 binding affinity (Kd) of 13.22 {micro}M. Notably, 10p overcomes previous developability hurdles by achieving a kinetic solubility of 758 {micro}M, a five-fold improvement over 11g. It further demonstrates high metabolic stability across species and no hERG inhibition. In 3D GBM spheroid models, 10p significantly reduced tumor viability, mass, and migration, exceeding the efficacy of prior analogues. Collectively, these findings establish 10p 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. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=124 SRC="FIGDIR/small/702243v1_ufig1.gif" ALT="Figure 1"> View larger version (30K): org.highwire.dtl.DTLVardef@dff733org.highwire.dtl.DTLVardef@1de4e56org.highwire.dtl.DTLVardef@1e910dcorg.highwire.dtl.DTLVardef@51e9d4_HPS_FORMAT_FIGEXP M_FIG C_FIG

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Kaur, B., Nada, H., Gabr, M.. 2026-01-30. Structural Optimization of CHI3L1 Inhibitors with Improved Pharmacokinetics and Functional Activity in 3D Glioblastoma Models. https://doi.org/10.64898/2026.01.28.702243

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