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 修复机制的理解的最新进展导致了 DNA 修复特异性核酸酶 Artemis 的鉴定。这种酶的突变不会影响活力，但会通过防止基于非同源末端连接 (NHEJ) 的 DNA 修复来增强细胞对电离辐射的敏感性。因此，抑制这种酶功能的小分子药物可能非常有用，可以作为增强癌症放射治疗同时保护正常组织的药物，从而不会对患者的生活质量产生不利影响。重要的是，在放疗之前、期间和之后给予 Artemis 抑制化合物应该使肿瘤细胞对辐射损伤敏感，无论治疗时的有丝分裂状态如何，从而有效杀死通常对放疗产生抵抗的生长缓慢的缺氧肿瘤细胞。该第一阶段申请描述了将筛选小分子库以鉴定 Artemis 活性抑制剂的研究。随后的二期申请将针对先导小分子候选物的开发和优化，这些候选物将在体外和体内进行测试，以确定这些化合物使肿瘤细胞对辐射损伤敏感的程度。第一阶段申请有三个具体目标： 1) 纯化足够数量的 Artemis 用于 HTS 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，寻找 Artemis 抑制剂。 3) 确定化合物对 Artemis 的特异性并获得特定化合物的 IC50 值。