Small Molecular Inhibitors of Artemis as Radiosensitizer

Artemis 小分子抑制剂作为放射增敏剂

• 批准号: 6833052
• 负责人: JOHN J HARRINGTON
• 金额: $ 9.99万
• 依托单位: ATHERSYS, INC.
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-08-01 至 2006-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6833052
• 关键词: DNA repair; HeLa cells; chemical registry /resource; drug discovery /isolation; enzyme activity; esterase inhibitor; ionizing radiation; neoplasm /cancer radiation therapy; nuclease; protein purification; radiosensitizer; small molecule

DESCRIPTION (provided by applicant): Recent advances in our understanding of DNA repair mechanisms have led to the identification of the DNA repair specific nuclease, Artemis. Mutations in this enzyme do not affect viability, but enhance cellular sensitivity to ionizing radiation through the prevention of non-homologous-end-joining (NHEJ)-based DNA repair. Hence, small molecule drugs inhibiting the function of this enzyme are likely to be extremely useful as agents to enhance radiotherapeutic treatment of cancer while sparing normal tissue, thereby not adversely affecting patient quality of life. Importantly, administration of Artemis inhibitory compounds before, during, and after radiotherapy should sensitize tumor cells to radiation damage regardless of mitotic state at the time of treatment, effectively killing slow growing hypoxic tumor cells which are normally resistant to radiotherapy. This phase I application describe studies that will result in the screening of a small molecule library to identify inhibitors of Artemis activity. The subsequent Phase II application will be directed toward development and optimization of lead small molecule candidates that will be tested in-vitro and in-vivo to determine the extent to which these compounds sensitize tumor cells to radiation damage. There are three specific aims for this phase I application: 1) Purify Artemis in sufficient quantities for HTS and optimize screening methods. 2) Screen a approximately 100,000-member small molecule compound library for inhibitors of Artemis. 3) Determine compound specificity toward Artemis and obtain IC50 values for specific compounds.

描述（由申请人提供）：我们对DNA修复机制的了解的最新进展导致了DNA修复特定核酸酶Artemis的鉴定。该酶中的突变不会影响生存能力，而是通过预防基于非同源的末端连接（NHEJ）基于基于的DNA修复来增强细胞对电离辐射的敏感性。因此，抑制该酶功能的小分子药物作为药物可能非常有用，可以增强癌症的放射治疗，同时保留正常组织，从而对患者的生活质量产生不利影响。重要的是，放疗前，期间和之后的牵引抑制性化合物的给药应使肿瘤细胞对辐射损伤敏感，而不论治疗时有丝分裂状态如何，有效地杀死了通常抗放射疗法的缓慢生长的低氧肿瘤细胞。该阶段的应用描述了将导致筛选小分子文库以鉴定Artemis活性抑制剂的研究。随后的II期应用将用于开发和优化铅小分子候选物，这些候选物将在体外和体内进行测试，以确定这些化合物在多大程度上使肿瘤细胞对辐射损伤敏感。该阶段的应用程序有三个具体目标： 1）用足够数量的HTS纯化Artemis并优化筛选方法。 2）筛选大约100,000名成员的小分子化合物库，用于artemis抑制剂。 3）确定对Artemis的复合特异性，并获得特定化合物的IC50值。