针对铜伴侣蛋白Atox1和CCS的新型抗肿瘤作用机制和化学干预功能调控研究

Copper chaperones Atox1 and CCS are key proteins for copper trafficking and homeostasis in organs. Increasing evidence suggests that Atox1 and CCS play significant role in cancer initiation and progression, so they have been recognized to be potential new targets for cancer therapy. In our recent studies, we reported a small molecule that inhibits the human Atox1 and CCS, providing an approach to selectively inhibiting cancer cell proliferation. However, the downstream mechanism of Atox1 and CCS are not completely understood in cancer cells. Therefore, we plan to further study the mechanism of Atox1 and CCS in cancer cells by combining chemical biology, bioinformatics and molecular biology. In addition, although we have multiple experiments to demonstrate both in vitro and in vivo effects of the previous inhibitor, we could not exclude the potential presence of other targets that may work synergistically with the inhibition of Atox1 and CCS due to its micromolar binding affinities. To resolve this issue, we will utilize structure-activity relationship analysis to design and obtain a series of novel Atox1 and CCS leading compounds, and then to explore the mechanism in protein, cells and animal models. Our research will improve the mechanism studies of Atox1 and CCS in cancer cells, and lay the foundation for further development of innovative drugs.

铜伴侣蛋白Atox1和CCS是负责铜离子在细胞内转运和维持细胞铜平衡的关键蛋白。研究发现Atox1和CCS的异常表达与多种肿瘤的发生发展密切相关，因此Atox1和CCS将会成为一类全新的抗肿瘤靶点。然而，目前Atox1和CCS在肿瘤细胞内的作用机制尚不清楚，并且缺乏高活性的先导化合物对其展开化学干预的功能调控研究。本项目在前期研究的基础上，一方面结合化学生物学、生物信息学和分子生物学等手段，围绕Atox1和CCS深入研究其在肿瘤细胞内的相关作用机制；另一方面，以发现的抑制剂为探针，围绕Atox1和CCS的结构与功能关系，运用构效关系和蛋白-小分子复合物晶体等研究手段，设计、发现新型先导化合物，在分子、细胞和动物水平进一步研究其作用机制。本项目不仅将揭示Atox1和CCS在肿瘤细胞内的作用机制和功能，也为针对铜紊乱导致的肿瘤治疗提供了药物先导结构，从而为开发相关药物奠定了基础。