Structural studies of metazoan origin licensing

后生动物起源许可的结构研究

• 批准号: 10604898
• 负责人: Olivia Hunker
• 金额: $ 4.77万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10604898
• 关键词: Amines; Amino Acids; Antineoplastic Agents; Binding; Binding Sites; Biochemical; Biological; Biological Assay; Biophysics; Cancer cell line; Cells; Clinical; Complex; Cryoelectron Microscopy; DNA; DNA Binding; DNA Replication Inhibition; DNA replication origin; Data; Development; Drug Design; Drug Targeting; Drug resistance; Dwarfism; Eukaryota; Event; Future; Goals; Human; In Vitro; Knowledge; Laboratories; Licensing; Link; Malignant Neoplasms; Mediating; Molecular; Mutation; Negative Staining; Pathway interactions; Patient-Focused Outcomes; Peptide Initiation Factors; Physiology; Play; Process; Replication Initiation; Replication Origin; Research; Role; Saccharomyces cerevisiae; Saccharomycetales; Site-Directed Mutagenesis; Structure; System; Testing; Therapeutic; Time; X-Ray Crystallography; cancer cell; cancer therapy; cofactor; cytotoxic; cytotoxicity; drug candidate; drug discovery; drug-like compound; helicase; improved; in vivo; inhibitor; insight; interest; mutant; new therapeutic target; novel; novel anticancer drug; origin recognition complex; prevent; reconstitution; replication stress; small molecule; small molecule inhibitor; tumor; tumor heterogeneity

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.

项目总结