Structural studies of metazoan origin licensing

项目摘要 由于肿瘤的异质性，开发有效的癌症治疗方法仍然是一个巨大的挑战。 生理学，对非癌细胞的细胞毒性，以及出现耐药性，所有这些都阻碍了 积极的病人结果。因此，迫切需要具有替代机制的新型抗癌药物 行动的一部分。靶向DNA复制起始途径是癌症治疗中一种未被探索的策略。 起源许可，DNA复制启动的第一步，在此过程中复制解旋酶Mcm2-7被 尤其令人感兴趣，因为它的抑制是选择性的细胞毒作用 癌细胞系。然而，还没有开发出用于临床治疗的原产地许可抑制剂，这是 部分原因是对后生动物中DNA复制启动的机制了解不完全。与…相反 酿酒酵母，已被广泛用于研究复制启动在生化和 在结构水平上，没有含有Mcm2-7的后生动物起源许可中间体的结构 解旋酶的负载问题已经解决。小分子来源许可抑制剂如何结合和抑制McM2-7 载荷系数同样是未知的。这些知识上的差距阻碍了有效药物的开发 目标是复制启动的候选对象。这项提案的目标是揭示结构性洞察 后生动物起源许可。对后生动物起源许可的深入理解将有助于 靶向DNA复制起始复合体和In的小分子抑制剂的研究进展 定义了这些抑制剂的作用机制。这些成果将有助于实现长期目标。 开发原产地许可抑制剂作为一类新的抗癌药物。

Project Summary Developing effective cancer therapies remains a significant challenge due to the heterogeneity of tumor physiology, cytotoxicity towards non-cancer cells, and the emergence of drug resistance, all of which hamper positive patient outcome. Thus, there is a critical need for novel anticancer agents with alternate mechanisms of action. Targeting the DNA replication initiation pathway is an underexplored strategy for cancer therapy. Origin licensing, the first step of DNA replication initiation during which the replicative helicase Mcm2-7 is loaded onto replication origins, is of particular interest because its inhibition is selectively cytotoxic towards cancer cell lines. However, no origin licensing inhibitors have been developed for clinical therapy yet, which is in part due to an incomplete mechanistic understanding of DNA replication initiation in metazoans. Contrary to S. cerevisiae, which has been used extensively to study replication initiation both at the biochemical and structural level, no structures of metazoan origin licensing intermediates containing Mcm2-7 on-pathway to helicase loading have been solved. How small-molecule origin licensing inhibitors bind and inhibit Mcm2-7 loading factors is likewise unknown. These gaps in knowledge have impeded the development of effective drug candidates targeting replication initiation. The goal of this proposal is to uncover structural insights into metazoan origin licensing. A deep understanding of metazoan origin licensing will aid in the development of small-molecule inhibitors targeting DNA replication initiation complexes and in defining the mechanisms by which these inhibitors act. These results will contribute to the long-term goal of developing origin licensing inhibitors as a new class of cancer drugs.