Simultaneous blockade of more than one pathway is considered to be a promising approach to overcome the low efficacy and acquired resistance of cancer therapies. Thus, a novel series of c-Met/HDAC bifunctional inhibitors was designed and synthesized by merging pharmacophores of c-Met and HDAC inhibitors. The most potent compound, 2m, inhibited c-Met kinase and HDAC1, with IC₅₀ values of 0.71 and 38 nM, respectively, and showed efficient antiproliferative activities against both EBC-1 and HCT-116 cells with greater potency than the reference drug Chidamide. Western blot analysis revealed that compound 2m inhibited phosphorylation of c-Met and c-Met downstream signaling proteins and increased expression of Ac-H3 and p21 in EBC-1 cells in a dose-dependent manner. Our study presents novel compounds for the further exploration of dual c-Met/HDAC pathway inhibition achieved with a single molecule.

中文翻译：

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基于哒嗪酮衍生物的首批c-Met / HDAC抑制剂的设计，合成和生物学评估

同时阻断多种途径被认为是克服癌症治疗的低药效和获得性耐药的一种有前途的方法。因此，通过合并c-Met和HDAC抑制剂的药效基团，设计和合成了一系列新的c-Met / HDAC双功能抑制剂。最有效的化合物2m抑制c-Met激酶和HDAC1，IC ₅₀值分别为0.71和38 nM，并显示出对EBC-1和HCT-116细胞的有效抗增殖活性，且比参考药物Chidamide具有更高的效力。免疫印迹分析表明化合物2m抑制c-Met和c-Met下游信号蛋白的磷酸化，并以剂量​​依赖的方式增加EBC-1细胞中Ac-H3和p21的表达。我们的研究提出了新的化合物，用于进一步探索用单个分子实现的双重c-Met / HDAC途径抑制作用。