Faculty of Pharmacy, Apotex Centre, University of Manitoba, 750 McDermot Avenue, Winnipeg, Manitoba R3E 0T5, Canada.
Biochem Pharmacol. 2012 Dec 15;84(12):1617-26. doi: 10.1016/j.bcp.2012.09.023. Epub 2012 Oct 5.
Dovitinib (TKI258/CHIR258) is a multi-kinase inhibitor in phase III development for the treatment of several cancers. Dovitinib is a benzimidazole-quinolinone compound that structurally resembles the bisbenzimidazole minor groove binding dye Hoechst 33258. Dovitinib bound to DNA as shown by its ability to increase the DNA melting temperature and by increases in its fluorescence spectrum that occurred upon the addition of DNA. Molecular modeling studies of the docking of dovitinib into an X-ray structure of a Hoechst 33258-DNA complex showed that dovitinib could reasonably be accommodated in the DNA minor groove. Because DNA binders are often topoisomerase I (EC 5.99.1.2) and topoisomerase II (EC 5.99.1.3) inhibitors, the ability of dovitinib to inhibit these DNA processing enzymes was also investigated. Dovitinib inhibited the catalytic decatenation activity of topoisomerase IIα. It also inhibited the DNA-independent ATPase activity of yeast topoisomerase II which suggested that it interacted with the ATP binding site. Using isolated human topoisomerase IIα, dovitinib stabilized the enzyme-cleavage complex and acted as a topoisomerase IIα poison. Dovitinib was also found to be a cellular topoisomerase II poison in human leukemia K562 cells and induced double-strand DNA breaks in K562 cells as evidenced by increased phosphorylation of H2AX. Finally, dovitinib inhibited the topoisomerase I-catalyzed relaxation of plasmid DNA and acted as a cellular topoisomerase I poison. In conclusion, the cell growth inhibitory activity and the anticancer activity of dovitinib may result not only from its ability to inhibit multiple kinases, but also, in part, from its ability to target topoisomerase I and topoisomerase II.
多韦替尼（TKI258/CHIR258）是一种处于 III 期开发阶段的多激酶抑制剂，用于治疗多种癌症。多韦替尼是一种苯并咪唑-喹啉酮化合物，在结构上类似于双苯并咪唑小沟结合染料 Hoechst 33258。多韦替尼与 DNA 结合，这一点可从其增加 DNA 熔点的能力以及加入 DNA 后荧光光谱的增加得到证明。多韦替尼与 Hoechst 33258-DNA 复合物的 X 射线结构对接的分子建模研究表明，多韦替尼可以合理地容纳在 DNA 小沟中。由于 DNA 结合剂通常是拓扑异构酶 I（EC 5.99.1.2）和拓扑异构酶 II（EC 5.99.1.3）抑制剂，因此还研究了多韦替尼抑制这些 DNA 加工酶的能力。多韦替尼抑制拓扑异构酶 IIα 的催化解链活性。它还抑制了酵母拓扑异构酶 II 的 DNA 非依赖性 ATP 酶活性，这表明它与 ATP 结合位点相互作用。使用分离的人拓扑异构酶 IIα，多韦替尼稳定了酶切割复合物，并作为拓扑异构酶 IIα 毒物起作用。多韦替尼还被发现是人白血病 K562 细胞中的细胞拓扑异构酶 II 毒物，并通过增加 H2AX 的磷酸化在 K562 细胞中诱导双链 DNA 断裂。最后，多韦替尼抑制了拓扑异构酶 I 催化的质粒 DNA 松弛，并作为细胞拓扑异构酶 I 毒物起作用。总之，多韦替尼的细胞生长抑制活性和抗癌活性不仅可能源于其抑制多种激酶的能力，而且部分可能源于其靶向拓扑异构酶 I 和拓扑异构酶 II 的能力。
