多靶点抗癌药物研究进展

Advances in design and discovery of multi-targeted anticancer drugs

多靶点抗癌药物可提高单靶点药物和多种药物联合用药的治疗效果,且有可能避免联合用药时产生的药物相互作用,降低副作用。在多靶点抗癌药物研究中,可采用"药效团拼合"的方法,将两种或两种以上的药效团拼合成一个分子,使其或其代谢产物作用于两个或两个以上靶点,从而产生协同作用,例如组蛋白去乙酰酶-酪氨酸激酶抑制剂和DNA损伤剂-EGFR抑制剂等。或者,根据靶标结合位点的相似性,设计与合成同时作用于两个或多个靶点的抗癌药物,例如VEGFR-PDGFR抑制剂和TS-DHFR双重抑制剂。本文将对这些多靶点抗癌药物的设计思路及生物活性进行归纳和总结。

Multi-targeted anticancer drugs have enhanced therapeutic effects over mono-targeted anticancer drugs or combined drugs. They can also avoid the drug interactions and reduce the side effects in the combined drug therapy. A multi-targeted anticancer drug could be constructed by incorporation of two or more pharmacoph- ores into one molecule, such as histone deacetylases-tyrosine kinase inhibitor, DNA-damaging agent-EGFR inhibi- tor, which or its metabolites can interact with two or more targets to achieve synergistic effects. Alternatively, a sin- gle molecule could be designed and synthesized to interact with two or more targets with the similar binding sites, for example, VEGFR-PDGFR inhibitor and TS-DHFR dual inhibitor. Herein, we summarized the design and biological activities of these multi-targeted anticancer drugs recently reported in literature.