Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center of Biotherapy, Chengdu, China.
Center of Gerontology and Geriatrics, West China Hospital, Sichuan University, Chengdu, China.
Chem Biol Drug Des. 2024 Jul;104(1):e14593. doi: 10.1111/cbdd.14593.
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 (IC = 8.22 ± 0.27 μM) showed better anti-tumor activity than the clinical Class I HDAC inhibitor MS-275 (IC = 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.
在现代癌症治疗中，阻断多个靶点是一种标准方法，已经有许多双靶点药物可以通过单个分子实现多种抑制。在此，我们通过结合基于信号转导和转录激活因子 3（STAT3）抑制剂 E28 和组蛋白去乙酰化酶（HDAC）抑制剂 MS-275 的药效团设计和合成了一系列具有 STAT3 和 HDAC 抑制活性的新型衍生物。其中，化合物 24（IC=8.22±0.27μM）在 MCF-7 乳腺癌细胞中的抗肿瘤活性优于临床 I 类 HDAC 抑制剂 MS-275（IC=14.65±0.24μM）。此外，通过 Western blot 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 STAT3-HDAC 通路抑制剂提供了新的工具化合物。
