Structure-Guided Discovery of CHI3L1 Inhibitors from Ultralarge Chemical Spaces for Glioblastoma Therapy
Abstract:
Glioblastoma (GBM) is the most aggressive primary brain tumor, with a median survival of approximately one year and limited therapeutic options. Chitinase 3-like 1 (CHI3L1) is increasingly recognized as a promising target in GBM due to its role in tumor progression and immune modulation. In this study, we employed an in-house structure-based screening strategy (SpaceDock) to explore a virtual chemical space of 377 billion compounds for potential CHI3L1 inhibitors. Using a reaction-aware ligand design approach, 60 top-scoring virtual hits were synthesized, and 45 were obtained with sufficient purity for experimental testing. Primary screening by microscale thermophoresis (MST) identified nine hits. Compounds showing dose-dependent binding were subsequently analyzed using surface plasmon resonance (SPR), leading to the identification of compound 9e with a dissociation constant ( K d ) of 19.11 µM. Importantly, 9e demonstrated robust, dose-dependent efficacy in a multicellular 3D GBM spheroid model, significantly reducing spheroid viability and downstream STAT3 signaling. These results highlight 9e as a promising drug candidate for modulating the CHI3L1-STAT3 axis and underscore the potential of structure-guided, reactivity-aware virtual screening of ultralarge chemical spaces to target non-enzymatic, conformationally dynamic proteins in complex cancer models.
Insights
Researchers identified a novel compound, 9e, that effectively inhibits Chitinase 3-like 1 (CHI3L1) in glioblastoma models. This discovery offers a promising new therapeutic strategy for aggressive brain tumors by targeting the CHI3L1-STAT3 pathway.
Area of Science:
- Oncology
- Pharmacology
- Biochemistry
Background:
- Glioblastoma (GBM) is an aggressive brain tumor with poor prognosis and limited treatment options.
- Chitinase 3-like 1 (CHI3L1) is implicated in GBM progression and immune evasion, making it a potential therapeutic target.
- Targeting CHI3L1 offers a novel strategy to overcome GBM's therapeutic resistance.
Purpose of the Study:
- To identify novel inhibitors of Chitinase 3-like 1 (CHI3L1) for glioblastoma treatment.
- To explore the efficacy of identified inhibitors in preclinical GBM models.
- To validate the potential of structure-guided virtual screening for drug discovery in oncology.
Main Methods:
- Utilized an in-house structure-based virtual screening platform (SpaceDock) to analyze 377 billion compounds.
- Employed a reaction-aware ligand design approach for hit identification.
- Synthesized and tested compounds using microscale thermophoresis (MST) and surface plasmon resonance (SPR) assays.
- Evaluated compound efficacy in a 3D GBM spheroid model, assessing viability and STAT3 signaling.
Main Results:
- Identified compound 9e as a potent CHI3L1 inhibitor with a Kd of 19.11 µM.
- Compound 9e demonstrated significant dose-dependent reduction in GBM spheroid viability.
- 9e effectively inhibited downstream STAT3 signaling in the 3D GBM model.
- Structure-guided, reactivity-aware virtual screening proved effective for targeting complex proteins.
Conclusions:
- Compound 9e is a promising drug candidate for targeting the CHI3L1-STAT3 axis in glioblastoma.
- The study validates the utility of ultralarge virtual screening for discovering novel cancer therapeutics.
- This approach holds potential for targeting non-enzymatic, dynamic proteins in complex disease models.
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