Abstract：
In modern cancer therapy, blockage of more than one target is a standard approach, and there are already many dual-target drugs that can achieve multiple inhibition through a single molecule. Herein, we designed and synthesized a series of novel derivatives with signal transducer and activator of transcription 3 (STAT3) and histone deacetylase (HDAC) inhibitory activity through strategy of combining pharmacophore based on the STAT3 inhibitor E28 and HDAC inhibitor MS-275. Among them, compound 24 (IC50 = 8.22 ± 0.27 μM) showed better anti-tumor activity than the clinical Class I HDAC inhibitor MS-275 (IC50 = 14.65 ± 0.24 μM) in MCF-7 breast cancer cells. Furthermore, the dual inhibition to HDAC and STAT3 of compound 24 was validated by western blot analysis. The study provides new tool compounds for further exploration of STAT3-HDAC pathway inhibitor achieved with a single molecule.
摘要：
在现代癌症治疗中，阻断多个目标是一种标准方法，并且已经有许多双靶标药物可以通过单个分子实现多重抑制。在这里，我们通过基于STAT3抑制剂E28和HDAC抑制剂MS-275的药效团组合策略，设计并合成了一系列具有信号转导和转录激活因子3（STAT3）和组蛋白去乙酰化酶（HDAC）抑制活性的新型衍生物。其中,化合物24(IC50=8.22±0.27μM)在MCF-7乳腺癌细胞中显示出比临床I类HDAC抑制剂MS-275(IC50=14.65±0.24μM)更好的抗肿瘤活性。此外，通过蛋白质印迹分析验证了化合物24对HDAC和STAT3的双重抑制作用.该研究为进一步探索用单个分子实现的STAT3-HDAC途径抑制剂提供了新的工具化合物。
