Abstract

Glioblastoma multiforme (GBM) is the most common and malignant primary brain tumour in the central nervous system (CNS). As the ideal targets for GBM treatment, Src family kinases (SFKs) have attracted much attention. Herein, a new series of imidazo[4,5-c]pyridin-2-one derivatives were designed and synthesised as SFK inhibitors. Compounds 1d, 1e, 1q, 1s exhibited potential Src and Fyn kinase inhibition in the submicromolar range, of which were next tested for their antiproliferative potency on four GBM cell lines. Compound 1s showed effective activity against U87, U251, T98G, and U87-EGFRvIII GBM cell lines, comparable to that of lead compound PP2. Molecular dynamics (MDs) simulation revealed the possible binding patterns of the most active compound 1s in ATP binding site of SFKs. ADME prediction suggested that 1s accord with the criteria of CNS drugs. These results led us to identify a novel SFK inhibitor as candidate for GBM treatment.

摘要

多形性胶质母细胞瘤 (GBM) 是中枢神经系统 (CNS) 中最常见和恶性的原发性脑肿瘤。作为 GBM 治疗的理想靶点，Src 家族激酶 (SFKs) 备受关注。在此，设计并合成了一系列新的咪唑并[4,5-c]pyridin-2-one衍生物作为SFK抑制剂。化合物1d、1e、1q、1s在亚微摩尔范围内表现出潜在的 Src 和 Fyn 激酶抑制作用，接下来测试它们对四种 GBM 细胞系的抗增殖效力。化合物1显示出对 U87、U251、T98G 和 U87-EGFRvIII GBM 细胞系的有效活性，与先导化合物 PP2 的活性相当。分子动力学 (MDs) 模拟揭示了SFKs ATP 结合位点中最活跃的化合物1s的可能结合模式。ADME预测表明1s符合CNS药物的标准。这些结果使我们确定了一种新型 SFK 抑制剂作为 GBM 治疗的候选者。