School of Pharmacy and Jiangsu Province Key Laboratory for Inflammation and Molecular Drug Target, Nantong University, Nantong 226001, China.
The Affiliated Hospital of Nantong University, Nantong University, Nantong 226001, China.
Curr Med Chem. 2020;27(42):7264-7288. doi: 10.2174/0929867327666200102115720.
Protein Kinase Inhibitors (PKIs) and Histone Deacetylase Inhibitors (HDACIs) are two important classes of anticancer agents and have provided a variety of small molecule drugs for the treatment of various types of human cancers. However, malignant tumors are of a multifactorial nature that can hardly be "cured" by targeting a single target, and treatment of cancers hence requires modulation of multiple biological targets to restore the physiological balance and generate sufficient therapeutic efficacy. Multi-target drugs have attracted great interest because of their advantages in the treatment of complex cancers by simultaneously targeting multiple signaling pathways and possibly leading to synergistic effects. Synergistic effects have been observed in the combination of kinase inhibitors, such as imatinib, dasatinib, or sorafenib, with an array of HDACIs including vorinostat, romidepsin, or panobinostat. A considerable number of multi-target agents based on PKIs and HDACIs have been developed. In this review, we summarize the recent literature on the development of multi-target kinase-HDAC inhibitors and provide our view on the challenges and future directions on this topic.
蛋白激酶抑制剂（PKIs）和组蛋白去乙酰化酶抑制剂（HDACIs）是两类重要的抗癌药物，为治疗各种类型的人类癌症提供了多种小分子药物。然而，恶性肿瘤具有多因素的性质，很难通过针对单一靶点来“治愈”，因此癌症的治疗需要调节多个生物靶点，以恢复生理平衡并产生足够的治疗效果。多靶点药物因其同时针对多个信号通路的优势而引起了极大的兴趣，并且可能产生协同作用。在激酶抑制剂（如伊马替尼、达沙替尼或索拉非尼）与多种 HDACIs（包括伏立诺他、罗米地辛或帕比司他）联合使用时已经观察到协同作用。已经开发了相当数量的基于 PKIs 和 HDACIs 的多靶点药物。在这篇综述中，我们总结了关于多靶点激酶-HDAC 抑制剂的最新文献，并对这一主题的挑战和未来方向提出了我们的看法。
