The activation of the STAT signal after incubation with the HDAC inhibitor represents a key mechanism causing resistance to HDAC inhibitors in some solid tumor cells, while the FGFR inhibitor could downregulate the level of pSTAT3. Inspired by the therapeutic prospect of FGFR/HDAC dual inhibitors, we designed and synthesized a series of quinoxalinopyrazole hydroxamate derivatives as FGFR/HDAC dual inhibitors. Among them, compound 10e potently inhibited FGFR1–4 and HDAC1/2/6/8 and presented improved antiproliferative effects of tumor cells. Further studies indicated that 10e also downregulated the expression of pSTAT3, potentially overcoming resistance to HDAC inhibitors. What’s more, 10e significantly inhibited the tumor growth in HCT116 and SNU-16 xenograft models with favorable pharmacokinetic profiles. Collectively, these results supported that 10e could be a new drug candidate for malignant tumors.

中文翻译：

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用于治疗癌症的成纤维细胞生长因子受体 (FGFR) 和组蛋白脱乙酰酶 (HDAC) 双重抑制剂的设计与合成

与 HDAC 抑制剂孵育后 STAT 信号的激活是导致某些实体瘤细胞对 HDAC 抑制剂产生耐药性的关键机制，而 FGFR 抑制剂可以下调 pSTAT3 的水平。受FGFR/HDAC双重抑制剂治疗前景的启发，我们设计合成了一系列喹喔啉基吡唑异羟肟酸酯衍生物作为FGFR/HDAC双重抑制剂。其中，化合物10e可有效抑制 FGFR1-4 和 HDAC1/2/6/8，并改善肿瘤细胞的抗增殖作用。进一步的研究表明，10e还下调了 pSTAT3 的表达，可能克服了对 HDAC 抑制剂的耐药性。更重要的是，10e显着抑制 HCT116 和 SNU-16 异种移植模型中的肿瘤生长，具有良好的药代动力学特征。总的来说，这些结果支持10e可能成为恶性肿瘤的新候选药物。