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Discovery of novel ID2 antagonists from pharmacophore-based virtual screening as potential therapeutics for glioma
Genshen Zhong1, Yichun Wang1, Qi Wang1
1Henan Key Laboratory of Immunology and Targeted Therapy, Henan Collaborative Innovation Center of Molecular Diagnosis and Laboratory Medicine, School of Laboratory Medicine, Xinxiang Medical University, Xinxiang, Henan 453003, China.
Abstract:
Glioma, especially the most aggressive type glioblastoma multiforme, is a malignant cancer of the central nervous system with a poor prognosis. Traditional treatments are mainly surgery combined with radiotherapy and chemotherapy, which is still far from satisfactory. Therefore, it is of great clinical significance to find new therapeutic agents. Serving as an inhibitor of differentiation, protein ID2 (inhibitor of DNA binding 2) plays an important role in neurogenesis, neovascularization and malignant development of gliomas. It has been shown that ID2 affects the malignant progression of gliomas through different mechanisms. In this study, a pharmacophore-based virtual screening was carried out and 16 hit compounds were purchased for pharmacological evaluations on their ID2 inhibitory activities. Based on the cytotoxicity of these small-molecule compounds, two compounds were shown to effectively inhibit the viability of glioma cells in the micromolar range. Among them, AK-778-XXMU was chosen for further study due to its better solubility in water. A SPR (Surface Plasma Resonance) assay proved the high affinity between AK-778-XXMU and ID2 protein with the KD value as 129 nM. The plausible binding mode of ID2 was studied by molecular docking and it was found to match AGX51 very well in the same binding site. Subsequently, the cancer-suppressing potency of the compound was characterized both in vitro and in vivo. The data demonstrated that compound AK-778-XXMU is a potent ID2 antagonist which has the potential to be developed as a therapeutic agent against glioma.
Insights
Researchers identified a novel compound, AK-778-XXMU, that effectively inhibits the protein ID2 (inhibitor of DNA binding 2). This compound shows potential as a new therapeutic agent for treating aggressive brain cancers like glioma.
Area of Science:
- Oncology
- Molecular Biology
- Drug Discovery
Background:
- Glioma, particularly glioblastoma multiforme, presents a significant challenge in central nervous system cancer treatment due to poor prognosis.
- Current therapies (surgery, radiotherapy, chemotherapy) offer limited efficacy, highlighting the need for novel therapeutic strategies.
- The protein ID2 (inhibitor of DNA binding 2) is implicated in glioma development, influencing neurogenesis, neovascularization, and malignancy.
Purpose of the Study:
- To identify and characterize novel small-molecule inhibitors of the ID2 protein for potential glioma therapy.
- To evaluate the efficacy of identified compounds against glioma cell viability and tumor progression.
Main Methods:
- Pharmacophore-based virtual screening to identify potential ID2 inhibitors.
- In vitro assessment of compound cytotoxicity and ID2 inhibitory activity.
- Surface Plasmon Resonance (SPR) assay to determine binding affinity (KD) between compound and ID2 protein.
- Molecular docking to elucidate the binding mode of the inhibitor.
- In vitro and in vivo studies to evaluate anti-cancer potency.
Main Results:
- Virtual screening yielded 16 hit compounds; two demonstrated significant glioma cell viability inhibition in the micromolar range.
- Compound AK-778-XXMU exhibited high affinity for ID2 protein (KD = 129 nM) and favorable solubility.
- Molecular docking suggested a binding mode consistent with known inhibitors.
- AK-778-XXMU demonstrated cancer-suppressing effects in both in vitro and in vivo models.
Conclusions:
- Compound AK-778-XXMU is a potent ID2 antagonist with demonstrated anti-glioma activity.
- AK-778-XXMU holds promise as a potential therapeutic agent for glioma treatment.
- Further development of AK-778-XXMU could lead to a new therapeutic option for patients with malignant brain tumors.
