Zhong Genshen, Wang Yichun, Wang Qi, Wu Minna, Liu Yichuang, Sun Shitao, Li Zhenli, Hao Jinle, Dou Peiyuan, Lin Bin
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.
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.
Bioorg Med Chem. 2021 Nov 1;49:116427. doi: 10.1016/j.bmc.2021.116427. Epub 2021 Sep 25.
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 K 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.
胶质瘤，尤其是最具侵袭性的多形性胶质母细胞瘤，是一种中枢神经系统恶性肿瘤，预后较差。传统治疗方法主要是手术联合放疗和化疗，但仍远不能令人满意。因此，寻找新的治疗药物具有重要的临床意义。蛋白质ID2（DNA结合抑制因子2）作为一种分化抑制因子，在神经发生、新血管形成和胶质瘤的恶性发展中起重要作用。已有研究表明，ID2通过不同机制影响胶质瘤的恶性进展。本研究基于药效团进行虚拟筛选，购买了16种活性化合物并对其ID2抑制活性进行药理学评价。基于这些小分子化合物的细胞毒性，有两种化合物在微摩尔范围内能有效抑制胶质瘤细胞的活力。其中，AK-778-XXMU因其在水中的溶解度较好而被选作进一步研究对象。表面等离子体共振（SPR）分析证明AK-778-XXMU与ID2蛋白具有高亲和力，K值为129 nM。通过分子对接研究了ID2可能的结合模式，发现其在相同结合位点与AGX51匹配良好。随后，对该化合物的抑癌效力进行了体外和体内表征。数据表明，化合物AK-778-XXMU是一种有效的ID2拮抗剂，有潜力开发成为抗胶质瘤的治疗药物。
