Background/Aim: A new class of imidazo[2,1-b][1,3,4]thiadiazole compounds have recently been evaluated as inhibitors of phosphorylation of focal adhesion kinase (FAK) in pancreatic cancer. FAK is overexpressed in mesothelioma and has recently emerged as an interesting target for the treatment of this disease. Materials and Methods: Ten imidazo[2,1-b][1,3,4]thiadiazole compounds characterized by indole bicycle and a thiophene ring, were evaluated for their cytotoxic activity in two primary cell cultures of peritoneal mesothelioma, MesoII and STO cells. Results: Compounds 1a and 1b showed promising antitumor activity with IC50 values in the range of 0.59 to 2.81 μM in both cell lines growing as monolayers or as spheroids. Their antiproliferative and antimigratory activity was associated with inhibition of phospho-FAK, as detected by a specific ELISA assay in STO cells. Interestingly, these compounds potentiated the antiproliferative activity of gemcitabine, and these results might be explained by the increase in the mRNA expression of the key gemcitabine transporter human equilibrative nucleoside transporter-1 (hENT-1). Conclusion: These promising results support further studies on new imidazo[2,1-b][1,3,4]thiadiazole compounds as well as on the role of both FAK and hENT-1 modulation in order to develop new drug combinations for peritoneal mesothelioma.

中文翻译：

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新型咪唑并[2,1-b] [1,3,4]噻二唑衍生物可抑制FAK磷酸化并通过调节人平衡性核苷转运蛋白-1在腹膜间皮瘤中增强吉西他滨的抗增殖作用

背景/目的：新型咪唑并[2,1-b] [1,3,4]噻二唑化合物最近被评估为胰腺癌中黏着斑激酶（FAK）磷酸化的抑制剂。FAK在间皮瘤中过表达，并且最近已成为治疗该疾病的有趣靶标。材料和方法：评价了十种咪唑并[2,1-b] [1,3,4]噻二唑化合物的特征是吲哚自行车和噻吩环在两种腹膜间皮瘤原代细胞，MesoII和STO细胞中的细胞毒活性。 。结果：化合物1a和1b在以单层或球状形式生长的两种细胞系中均显示出令人满意的抗肿瘤活性，IC50值在0.59至2.81μM的范围内。它们的抗增殖和抗迁移活性与磷酸化FAK的抑制作用有关，如通过STO细胞中的特异性ELISA检测所检测到的。有趣的是，这些化合物增强了吉西他滨的抗增殖活性，这些结果可能由关键的吉西他滨转运蛋白人平衡核苷转运蛋白-1（hENT-1）的mRNA表达增加所解释。结论：这些有希望的结果支持对新的咪唑并[2,1-b] [1,3,4]噻二唑化合物以及FAK和hENT-1调节作用的进一步研究，以开发用于腹膜的新药组合间皮瘤。