Targeting the DNA repair enzyme apurinic/apyrimidinic endonuclease (APE1) to treat cancer

靶向 DNA 修复酶无嘌呤/无嘧啶核酸内切酶 (APE1) 来治疗癌症

• 批准号: 10079779
• 负责人: Patricia Pellicena
• 金额: $ 29.77万
• 依托单位: XPOSE THERAPEUTICS, INC.
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-01 至 2022-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10079779
• 关键词: Active Sites; Affect; Base Excision Repairs; Biochemical; Biological; Biological Assay; Biophysics; Cells; Chemical Structure; Clinic; Crystallization; Crystallography; DNA; DNA Damage; DNA Repair; DNA Repair Enzymes; Development; Disease Progression; Disease Resistance; Drug resistance; Enzymes; Exposure to; Future; Generations; Goals; Growth; Human; In Vitro; Individual; Lead; Malignant Neoplasms; Metabolism; Mutagens; Participant; Pathway interactions; Patients; Pharmaceutical Chemistry; Pharmaceutical Preparations; Phase; Positioning Attribute; Property; Proteins; Resolution; Site; Structure; Synthesis Chemistry; Therapeutic; TimeLine; X-Ray Crystallography; base; cancer cell; cancer survival; cancer therapy; chemotherapeutic agent; clinical investigation; computational chemistry; design; drug discovery; endonuclease; follow-up; inhibitor/antagonist; migration; molecular modeling; neoplastic cell; novel; overexpression; phase 1 study; phase 2 study; pre-clinical; preclinical study; replication stress; response; screening; stem; structural biology; three dimensional structure; tumor

Cells respond to increases in DNA damage by upregulating their DNA damage response (DDR) pathways. Replicative stress, increased cellular metabolism and exposure to chemotherapeutic agents all contribute to elevated levels of DNA damage in cancer cells. The base excision repair (BER) pathway corrects damage to single DNA bases through the action of several enzymes, including the central participant, apurinic/apyrimidinic endonuclease 1 (APE1). Several studies have demonstrated an association between increased APE1 levels and enhanced growth, migration, and drug resistance in human tumor cells, as well as with decreased patient survival overall. To date, APE1 has been implicated in over 20 human cancers, making this enzyme an attractive target for the development of future anticancer therapies. There are currently no inhibitors of the DNA repair activity of APE1 in the clinic. A newly developed high-throughput crystallography-based fragment screen has resulted in high resolution crystal structures of chemical fragments bound to the endonuclease site of APE1. These are the first experimental 3D structures of APE1 bound to drug-like molecules, thereby resolving a primary bottleneck in the path to inhibitor development. In this Phase I study, we propose to elaborate these fragment hits into inhibitors of APE1 through a combination of computational and medicinal chemistry, structural biology, and biochemical and biophysical assays. Completion of this Phase I proposal will enable a Phase II application to expand the SAR and optimize the drug-like properties of the lead compound.

细胞通过上调DNA损伤反应（DDR）途径来应对DNA损伤的增加。