2. Academic Validation
  3. Discovery of novel ID2 antagonists from pharmacophore-based virtual screening as potential therapeutics for glioma

Discovery of novel ID2 antagonists from pharmacophore-based virtual screening as potential therapeutics for glioma

  • Bioorg Med Chem. 2021 Nov 1;49:116427. doi: 10.1016/j.bmc.2021.116427.
Genshen Zhong 1,  Yichun Wang 2,  Qi Wang 2,  Minna Wu 3,  Yichuang Liu 4,  Shitao Sun 4,  Zhenli Li 4,  Jinle Hao 4,  Peiyuan Dou 5,  Bin Lin 6
Affiliations

Affiliations

  • 1 Henan 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. Electronic address: [email protected].
  • 2 Henan 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.
  • 3 School of Basic Medicine, Xinxiang Medical University, Xinxiang, Henan 453003, China.
  • 4 School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Shenyang, Liaoning 110016, China.
  • 5 School of Chemistry, Cardiff University, Cardiff CF10 3AT, United Kingdom.
  • 6 School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Shenyang, Liaoning 110016, China. Electronic address: [email protected].
PMID: 34600240 DOI: 10.1016/j.bmc.2021.116427
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.

Keywords

Glioma; Inhibitor of differentiation; Pharmacophore; Virtual screening.

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