SCREENING AND COMPOUND EVALUATION

筛选和化合物评估

• 批准号: 6203322
• 负责人: MICHAEL R KOZLOWSKI
• 金额: $ 15.02万
• 依托单位: GERON CORPORATION
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-09-17 至 2000-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6203322
• 关键词: antineoplastics; bioassay; chemical kinetics; clone cells; cooperative study; drug discovery /isolation; drug screening /evaluation; enzyme activity; enzyme inhibitors; telomerase

Tumor cells possess the capacity for unlimited replication. This immortal phenotype is, ultimately, the reason why they produce death in cancer patients. Clinically used and-cancer regimens, as well as those under experimental evaluation, generally attempt to contain this growth potential either through reducing the tumor burden (e.g., with surgery, cytotoxic/cytostatic agents, or radiation), manipulating the environment of the tumor, or attempting to reinstate cell cycle controls. Telomerase inhibition is the only therapeutic target that aims at reversing the immortal phenotype of tumor cells. Because of the novelty of this approach, no telomerase inhibitors have yet been developed for human therapeutic use. Furthermore the complete human enzyme has not yet been purified or cloned. Thus, it is not possible at this point to design telomerase inhibitors rationally. An empirical approach using high-throughput screening will, therefore, be used to discover telomerase inhibitors. Active compounds will also be profiled in secondary assays to establish their specificity. Successive rounds of chemical modification followed by testing in the screen and secondary assays will be used to improve the potency and specificity of the most promising compound(s). When sufficient potency and specificity are achieved, the compound will be tested in ex vivo, and, finally, in vivo tumor models.

肿瘤细胞具有无限复制的能力。这 最终，不朽的表型是它们产生死亡的原因 在癌症患者中。临床上使用的癌症治疗方案，以及 那些正在接受实验评估的人，通常会试图遏制这种情况 通过减少肿瘤负荷来增加生长潜力（例如， 手术、细胞毒性/细胞抑制剂或放射），操纵 肿瘤的环境，或试图恢复细胞周期 控制。端粒酶抑制是唯一的治疗靶点 旨在逆转肿瘤细胞的永生表型。由于 这种方法的新颖之处在于，目前还没有端粒酶抑制剂被开发出来。 为人类治疗用途而开发。此外，完整的人类 酶尚未被纯化或克隆。因此，不可能 此时要合理设计端粒酶抑制剂。经验主义 因此，使用高通量筛选的方法将用于 发现端粒酶抑制剂。活性化合物也将被分析 在二次测定中以确定其特异性。连续几轮 化学修饰，然后在屏幕上进行测试 二次测定将用于提高效力和特异性 最有前途的化合物。当足够的效力和 达到特异性后，该化合物将在体外进行测试，并且， 最后，体内肿瘤模型。