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Virtual Screening-Guided Discovery of Small-Molecule CHI3L1 Inhibitors with Functional Activity in Glioblastoma
Baljit Kaur1, Katrin Denzinger2, Longfei Zhang1
1Department of Radiology, Molecular Imaging Innovations Institute (MI3), Weill Cornell Medicine, New York, New York 10065, United States.
Abstract:
Chitinase-3-like protein 1 (CHI3L1), a glycoprotein implicated in inflammation and cancer, has emerged as a therapeutic target for glioblastoma (GBM). CHI3L1 contributes to tumor progression and immune evasion by promoting STAT3 signaling and mesenchymal transition. To identify small-molecule CHI3L1 inhibitors, a structure-based 3D pharmacophore model was developed and applied to virtually screen over 4.4 million compounds. We selected 35 candidates for experimental evaluation. Binding validation via MST confirmed dose-dependent CHI3L1 interactions for two compounds, 8 and 39, with dissociation constants (K d) of 6.8 μM and 22 μM, respectively. These CHI3L1 affinities were further supported by SPR-based screening. In 3D GBM spheroid models, compound 8 reduced spheroid viability and attenuated phospho-STAT3 levels, consistent with CHI3L1 pathway disruption. Compared to the previously reported CHI3L1 inhibitors, compound 8 demonstrates superior CNS pharmacokinetics, inhibition of STAT3 and angiogenesis, and enhanced efficacy in GBM spheroids, establishing it as a more translationally viable scaffold.
Insights
Researchers identified novel small-molecule inhibitors for Chitinase-3-like protein 1 (CHI3L1), a key target in glioblastoma (GBM). Compound 8 shows promising efficacy and pharmacokinetic properties for GBM treatment.
Area of Science:
- Biochemistry
- Oncology
- Pharmacology
Background:
- Chitinase-3-like protein 1 (CHI3L1) is implicated in glioblastoma (GBM) progression and immune evasion.
- CHI3L1 promotes tumor growth by activating STAT3 signaling and mesenchymal transition.
Purpose of the Study:
- To identify novel small-molecule inhibitors of CHI3L1 for glioblastoma therapy.
- To develop and validate a structure-based pharmacophore model for virtual screening.
Main Methods:
- Utilized a structure-based 3D pharmacophore model to screen over 4.4 million compounds.
- Experimentally evaluated 35 candidate compounds using MicroScale Thermophoresis (MST) and Surface Plasmon Resonance (SPR).
- Assessed compound efficacy in 3D glioblastoma spheroid models, measuring viability and STAT3 phosphorylation.
Main Results:
- Identified two CHI3L1 inhibitors, compounds 8 and 39, with dissociation constants (Kd) of 6.8 μM and 22 μM, respectively.
- Compound 8 demonstrated dose-dependent inhibition of CHI3L1 activity.
- In GBM spheroids, compound 8 reduced viability, decreased phospho-STAT3 levels, and showed improved CNS pharmacokinetics and anti-angiogenic effects compared to existing inhibitors.
Conclusions:
- Compound 8 is a promising therapeutic candidate for glioblastoma, exhibiting potent CHI3L1 inhibition and favorable preclinical properties.
- The identified CHI3L1 inhibitors represent a translationally viable scaffold for GBM treatment development.
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