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Discovery of small molecule CHI3L1 inhibitors by SPR-based high-throughput screening
Longfei Zhang1, Hossam Hammouda Nada Hammouda1, Moustafa T Gabr1
1Department of Radiology, Molecular Imaging Innovations Institute (MI3), Weill Cornell Medicine, New York, NY 10065, USA.
Abstract:
Chitinase-3-like 1 (CHI3L1) is a secreted glycoprotein implicated in carcinogenesis and tumor immune evasion. Elevated CHI3L1 expression is frequently detected in cancer patients, highlighting it as a promising therapeutic target. To overcome the limited availability of small molecule CHI3L1 inhibitors, we established a surface plasmon resonance (SPR)-based high-throughput screening platform and applied it to a focused chemical library of small molecules. Primary screening identified seven hits, with compounds 1-4 and 1-7 validated as CHI3L1 binders (Kd = 10.4 ± 1.0 μM and 7.40 ± 0.78 μM, respectively). Both compounds disrupted the CHI3L1-galectin-3 interaction in AlphaLISA assays and engaged the CHI3L1 binding pocket in docking and molecular dynamics (MD) simulations. Importantly, functional evaluation in a multicellular 3D glioblastoma (GBM) spheroid model demonstrated that compound 1-7 potently reduced spheroid viability and inhibited STAT3 phosphorylation, outperforming both compound 1-4 and the known CHI3L1-STAT3 disruptor hygromycin B (HB). These findings validate SPR as a robust primary screening platform for CHI3L1 and demonstrate that the identified small molecule binders exert functional activity in a physiologically relevant multicellular GBM spheroid model.
Insights
Researchers developed a high-throughput screening method to find small molecule inhibitors for Chitinase-3-like 1 (CHI3L1), a protein linked to cancer. They identified effective CHI3L1 binders that reduce glioblastoma cell viability and inhibit STAT3 phosphorylation.
Area of Science:
- Biochemistry
- Oncology
- Drug Discovery
Background:
- Chitinase-3-like 1 (CHI3L1) is a protein associated with cancer development and immune evasion.
- High CHI3L1 levels in cancer patients indicate its potential as a therapeutic target.
- Limited availability of small molecule CHI3L1 inhibitors necessitates novel screening approaches.
Purpose of the Study:
- To establish a surface plasmon resonance (SPR)-based high-throughput screening platform for CHI3L1 inhibitors.
- To identify and validate small molecules that inhibit CHI3L1 activity and function.
- To evaluate the efficacy of identified compounds in a glioblastoma (GBM) model.
Main Methods:
- High-throughput screening using SPR to identify CHI3L1 binders from a chemical library.
- Biochemical assays (AlphaLISA) to confirm CHI3L1-galectin-3 interaction disruption.
- Molecular docking and dynamics simulations to analyze compound binding.
- Functional assays in 3D GBM spheroid models to assess compound efficacy.
Main Results:
- Seven initial hits were identified, with compounds 1-4 and 1-7 validated as CHI3L1 binders.
- Both compounds disrupted the CHI3L1-galectin-3 interaction and bound to the CHI3L1 pocket.
- Compound 1-7 significantly reduced GBM spheroid viability and inhibited STAT3 phosphorylation, outperforming other tested compounds.
Conclusions:
- SPR is a validated platform for primary screening of CHI3L1 inhibitors.
- Identified small molecules demonstrate functional activity in a relevant GBM model.
- The findings support the development of CHI3L1 inhibitors for cancer therapy.
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