Dysregulation of anaplastic lymphoma kinase (ALK) has been detected in nonsmall cell lung cancer (NSCLC) in the form of EML4-ALK fusion. Secondary mutations opposing activity of the first-generation ALK inhibitor crizotinib came into existence, requiring mutation-targeting drug discovery for the powerful second-line treatment. In this study, we report 4-phenoxyquinoline-based inhibitors that overcome crizotinib resistance to ALK L1196M, discovered by the fragment-growing strategy. The protonation of 4-aminoquinoline core could interrupt the ability the N atom of quinoline to act as a hydrogen bond acceptor; therefore, the pK_a and calculated ionization pH values of relevant pyridine-based core moieties were carefully analyzed. The replacement of amine linkage with ether resulted in single-digit nanomolar range inhibitors. The inhibitors exhibited significant antiproliferative effects on H2228 CR crizotinib-resistant cells by decreasing PI3K/AKT and MAPK signaling. This work constitutes the first example for systematic investigation of the effect of ionization pH on activity in this system.

中文翻译：

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基于结构的设计鉴定基于4-苯氧基喹啉的L1196M突变性间变性淋巴瘤激酶突变体的抑制剂

在非小细胞肺癌（NSCLC）中已检测到以EML4-ALK融合形式出现的变性淋巴瘤激酶（ALK）失调。与第一代ALK抑制剂crizotinib的活性相反的二级突变应运而生，这就需要发现靶向突变的药物来进行有效的二线治疗。在这项研究中，我们报告了基于4-苯氧基喹啉的抑制剂，该抑制剂克服了克唑替尼对片段增长策略发现的对ALK L1196M的抗性。4-氨基喹啉核心的质子化可能会中断喹啉的N原子作为氢键受体的能力。因此，p K _a并仔细分析了相关吡啶基核心部分的计算电离pH值。用醚取代胺键产生了一位数的纳摩尔范围抑制剂。通过降低PI3K / AKT和MAPK信号传导，这些抑制剂对H2228 CR crizotinib耐药细胞表现出显着的抗增殖作用。这项工作构成了系统研究电离pH值对该系统活性的影响的第一个例子。