Synthesis and Bioevaluation of 3-(Arylmethylene)indole Derivatives: Discovery of a Novel ALK Modulator with Antiglioblastoma Activities
Synthesis and Bioevaluation of 3-(Arylmethylene)indole Derivatives: Discovery of a Novel ALK Modulator with Antiglioblastoma Activities
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DOI：
10.1021/acs.jmedchem.3c01090
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发表时间：
2023-10-20
影响因子：
7.3
通讯作者：
Chen，Dongyin
中科院分区：
文献类型：
--
作者：
Feng，Lili;Chen，Xiang;Chen，Dongyin
胶质母细胞瘤是最常见的脑肿瘤，复发率高，生存率低。综合生物信息学分析表明，间变性淋巴瘤激酶（ALK）是胶质母细胞瘤的一个有前途的治疗靶点。我们设计并合成了一系列3-（芳基亚甲基）吲哚衍生物，并利用神经胶质瘤细胞系进一步评估其抗增殖活性。其中，化合物4a显著抑制胶质母细胞瘤细胞的活力。4a具有良好的药代动力学特性和血脑屏障通透性，可提高原位胶质母细胞瘤的存活率并抑制其生长。Phospho-Totum系统显示ALK是4a抗胶质母细胞瘤活性的潜在靶点。进一步的实验表明，4 a可能是一种新型的ALK调节剂，它与ALK的胞外配体结合结构域相互作用，从而选择性地诱导ERK介导的自噬和凋亡。我们的研究结果提供了一种替代的基于ALK的靶向策略和胶质母细胞瘤治疗的新候选药物。
Glioblastoma is the most common brain tumor, with high recurrence and low survival rates. An integrative bioinformatics analysis demonstrated that anaplastic lymphoma kinase (ALK) is a promising therapeutic target for glioblastoma. We designed and synthesized a series of 3-(arylmethylene)indole derivatives, which were further evaluated for antiproliferative activity using glioma cell lines. Among them, compound4asignificantly inhibited the viability of glioblastoma cells. With favorable pharmacokinetic characteristics and blood–brain barrier permeability,4aimproved the survival rate and inhibited the growth of orthotopic glioblastoma. The Phospho-Totum system revealed that ALK was a potential target for the antiglioblastoma activity of4a. Further experiments indicated that4amight be a novel ALK modulator, which interacted with the extracellular ligand-binding domain of ALK, thus selectively induced ERK-mediated autophagy and apoptosis. Our findings provide an alternative ALK-based targeting strategy and a new drug candidate for glioblastoma therapy.