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Virtual Screening-Guided Discovery of Small Molecule CHI3L1 Inhibitors with Functional Activity in Glioblastoma
Abstract:
Chitinase-3-like protein 1 (CHI3L1), a glycoprotein implicated in inflammation, fibrosis, and cancer, has emerged as a potential 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 from the Enamine collection. Following multi-tiered filtering, 35 candidates were selected for experimental evaluation. Binding validation via microscale thermophoresis (MST) confirmed dose-dependent CHI3L1 interactions for two compounds, 8 and 39, with dissociation constants (Kd) of 6.8 μM and 22 μM, respectively. These affinities were further supported by surface plasmon resonance (SPR), which yielded Kd values of 5.69 μM for compound 8 and 17.09 μM for compound 39. In 3D GBM spheroid models, compound 8 significantly reduced spheroid viability and attenuated phospho-STAT3 levels, consistent with CHI3L1 pathway disruption. These findings identify two promising scaffolds and support the utility of pharmacophore-guided virtual screening for discovering functionally active ligands targeting CHI3L1 in GBM.
Insights
Researchers identified small molecules targeting Chitinase-3-like protein 1 (CHI3L1) for glioblastoma treatment. Two compounds showed promising binding affinity and inhibited tumor cell viability, validating a structure-based drug discovery approach for CHI3L1 inhibitors.
Area of Science:
- Biochemistry
- Oncology
- Drug Discovery
Background:
- Chitinase-3-like protein 1 (CHI3L1) is a glycoprotein involved in inflammation, fibrosis, and cancer.
- CHI3L1 promotes glioblastoma (GBM) progression and immune evasion via STAT3 signaling and mesenchymal transition.
- CHI3L1 represents a potential therapeutic target for GBM.
Purpose of the Study:
- To identify novel small molecule inhibitors of CHI3L1.
- To validate a structure-based 3D pharmacophore model for virtual screening.
- To assess the efficacy of identified inhibitors in GBM models.
Main Methods:
- Development of a structure-based 3D pharmacophore model for CHI3L1.
- Virtual screening of over 4.4 million compounds from the Enamine collection.
- Experimental validation using microscale thermophoresis (MST) and surface plasmon resonance (SPR).
- Evaluation of compound activity in 3D GBM spheroid models.
Main Results:
- Two compounds, 8 and 39, demonstrated dose-dependent binding to CHI3L1 with Kd values in the micromolar range (5.69–17.09 μM).
- Compound 8 significantly reduced GBM spheroid viability.
- Compound 8 attenuated phospho-STAT3 levels, indicating CHI3L1 pathway inhibition.
Conclusions:
- The study identified two promising small molecule scaffolds targeting CHI3L1.
- Pharmacophore-guided virtual screening is an effective strategy for discovering functional CHI3L1 inhibitors.
- These findings support CHI3L1 as a therapeutic target for glioblastoma.
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