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。 复制应激、细胞代谢增加和接触化疗药物都会导致 癌细胞中 DNA 损伤水平升高。碱基切除修复 (BER) 途径可纠正损伤 通过几种酶的作用形成单个 DNA 碱基，包括中心参与者，无嘌呤/无嘧啶 核酸内切酶 1 (APE1)。多项研究表明 APE1 水平升高与 增强人类肿瘤细胞的生长、迁移和耐药性，并降低患者生存率 全面的。迄今为止，APE1 已与 20 多种人类癌症有关，使这种酶成为有吸引力的靶标 以开发未来的抗癌疗法。目前尚无 DNA 修复活性抑制剂 APE1 在诊所。新开发的基于高通量晶体学的片段筛选已产生 与 APE1 核酸内切酶位点结合的化学片段的高分辨率晶体结构。这些是 第一个实验性的 APE1 3D 结构与类药物分子结合，从而解决了 抑制剂开发之路。在这项第一期研究中，我们建议将这些片段命中精心设计成抑制剂 通过计算和药物化学、结构生物学和生物化学的结合来研究 APE1 和生物物理测定。第一阶段提案的完成将使第二阶段申请能够扩大 SAR 并优化先导化合物的药物特性。