Standard chemotherapy and personalized target therapies are commonly used in patients with advanced non-small cell lung cancer (NSCLC). However, multidrug resistance (MDR) and tumor metastasis lead to the decline of therapeutic efficacy, which are closely related to epithelial-mesenchymal transition (EMT). Twist1, an EMT transcription factor, plays an essential role in promoting EMT, MDR and tumor metastasis. In view of the essential role of Twist1 in the tumorigenesis of NSCLC, developing antitumor small molecules that can suppress the expression of Twist1 is of far-reaching significance for the treatment of NSCLC. A series of novel benzo[d]imidazo[2,1-b]thiazole derivatives possessing 1,3,4-oxadiazole moiety were designed based on the structure of the first-in-class Twist1 inhibitor harmine. Among the synthetic twenty-two compounds, the compound containing 2-(piperidine-1-yl) ethyl exhibited remarkable anti-proliferative activity with IC₅₀ value of 2.03 μM and 9.80 μM against A549 and H2228 cell lines superior to harmine (IC₅₀ = 17.12 μM against A549, IC₅₀ = 31.06 μM against H2228). Meanwhile, western blot assay showed that the optimal compound significantly down-regulated Twist1 protein expression in a dose-dependent manner and reduced Twist1 level better than harmine. Collectively, the promising compound was identified a potential antineoplastic lead with the ability of down-regulating Twist1 level.

标准化疗和个性化靶向治疗常用于晚期非小细胞肺癌 (NSCLC) 患者。然而，多药耐药（MDR）和肿瘤转移导致治疗效果下降，这与上皮间质转化（EMT）密切相关。Twist1 是一种 EMT 转录因子，在促进 EMT、MDR 和肿瘤转移中起重要作用。鉴于Twist1在NSCLC肿瘤发生中的重要作用，开发能够抑制Twist1表达的抗肿瘤小分子对于NSCLC的治疗具有深远意义。一系列新型苯并[ d ]咪唑并[2,1- b]基于一流的Twist1抑制剂harmine的结构设计了具有1,3,4-恶二唑部分的噻唑衍生物。在合成的22种化合物中，含有2-(哌啶-1-基)乙基的化合物表现出显着的抗增殖活性，对A549和H2228细胞系的IC ₅₀值分别为2.03 μM和9.80 μM，优于harmine (IC ₅₀  = 17.12 μM 对抗 A549，IC ₅₀  = 31.06 μM 对抗 H2228）。同时，蛋白质印迹试验表明，最佳化合物以剂量依赖性方式显着下调 Twist1 蛋白的表达，并且比harmine 更好地降低 Twist1 水平。总的来说，这种有前景的化合物被鉴定为具有下调 Twist1 水平能力的潜在抗肿瘤先导物。