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bioRxiv · 10.64898/2026.10.20.760326

Resistance-Mutant Rescue Establishes On-Target CHI3L1 Inhibition by CHI-DEL, a Brain-Penetrant Small Molecule with In Vivo Efficacy in Glioblastoma

Upadhyay, S.·Zhang, L.·Teplova, M.·Khan, S.·Gabr, M.
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Abstract

CHI3L1 (YKL-40) drives glioblastoma progression and immunosuppressive neuroimmune signaling, but as a non-enzymatic secreted glycoprotein it has lacked a genetic tool to confirm that small molecule effects are truly on-target. From a DNA-encoded small molecule library we identify CHI-DEL, a potent CHI3L1 ligand, and solve a 2.81 [A] co-crystal structure (PDB 10JV) revealing a binding trajectory centered on Trp99. Structure-guided mutagenesis yields W99F, a compound-resistant CHI3L1 allele that retains native secretion, basal signaling, and thermal stability, unlike the destabilizing W99A control, establishing a clean chemical-genetic separation of biology from drug sensitivity. In isogenic knockout/rescue cells, wild-type rescue restores both phenotype and CHI-DEL sensitivity across invasion, proliferation, and a multi-node signaling program (pSTAT3 and NF-{kappa}B), while W99F rescue restores phenotype but confers resistance to CHI-DEL that is complete for some readouts and partial for others. This same epistasis was reproduced in human iPSC-derived microglia, where CHI-DEL reverses a GBM-conditioned-medium-induced phenotype in a CHI3L1- and Trp99-dependent manner. In vivo, CHI-DEL achieves brain and tumor exposure, engages its target and disrupts CHI3L1-CD44 signaling in a dose-dependent manner, remodels the tumor immune microenvironment, and confers a dose-dependent survival benefit that is specific to the active compound. Together, these data extend CHI3L1 small molecule inhibitor development beyond in vitro optimization, providing genetic proof of on-target pharmacology and a brain-penetrant therapeutic strategy for glioblastoma.

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Upadhyay, S., Zhang, L., Teplova, M., Khan, S., Gabr, M.. 2026-10-24. Resistance-Mutant Rescue Establishes On-Target CHI3L1 Inhibition by CHI-DEL, a Brain-Penetrant Small Molecule with In Vivo Efficacy in Glioblastoma. https://doi.org/10.64898/2026.10.20.760326

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