Topoisomerase Targeting Agents Predicated on Polyamine Architectures

基于多胺结构的拓扑异构酶靶向剂

• 批准号: 7535409
• 负责人: GUN E LEE
• 金额: $ 15.36万
• 依托单位: TOPOGEN, INC.
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-07-14 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7535409
• 关键词: Address; Adverse effects; Antineoplastic Agents; Architecture; Biochemistry and Pharmacology Cancer Activity; Biological Assay; Cell Line; Cells; Chemistry; Collaborations; Complex; Condition; Coupled; Coupling; DNA; DNA Binding Agent; DNA Damage; DNA topoisomerase II alpha; Data; Development; Diagnostics Research; Dose; Drug Delivery Systems; Drug Design; End Point; Enzymes; Evaluation; Florida; Future; Genomics; Growth; Growth Factor; In Vitro; Laboratories; Libraries; Life; Malignant - descriptor; Malignant Neoplasms; Marketing; Measures; Mediating; Medical Economics; Modeling; Normal Cell; Numbers; Outcome; Pathway interactions; Pharmaceutical Preparations; Pharmaceutical Technology; Pharmacologic Substance; Phenotype; Poison; Poisoning; Polyamines; Population; Process; Production; Proliferating; Prostate; Protein Overexpression; Public Health; Reagent; Research; Research Personnel; Small Business Funding Mechanisms; Small Business Innovation Research Grant; Somatic Cell; Sorting - Cell Movement; Specificity; Spermine; Staging; System; Technology; Therapeutic; Thinking; Tissues; Topoisomerase; Topoisomerase II; United States Food and Drug Administration; Universities; base; cancer cell; cancer therapy; cancer type; cell growth; cell killing; cell type; chemotherapeutic agent; chemotherapy; combinatorial; concept; cost; design; experience; improved; in vitro Assay; in vivo; killings; member; novel; novel strategies; scaffold; small molecule; text searching; tumor; uptake

DESCRIPTION (provided by applicant): Drugs that target topoisomerase action are effective anticancer agents and a number are FDA approved. Anti-topoisomerase therapy is predicated on subverting the endogenous topoisomerase into a genotoxic, DNA damaging agent. A significant problem with such drugs is collateral damage in normal cells. Since all nucleated somatic cells retain some level topoisomerase activity (either type I and/or type II), negative outcome due to DNA damage in normal healthy tissue is unavoidable, unless novel strategies can be crafted to tune down undesirable side effects. In this SBIR, the corporate sponsor (TopoGEN, Inc.) is proposing a combinatorial strategy using `smart pharma' drug design. Potent topoisomerase poisons can be coupled to polyamines (spermine for example) which are processed preferentially by cancer cells based on elevated requirement of exogenous polyamines for cell growth. Evidence is provided that novel anti- topoisomerase/polyamine conjugates induce preferential DNA damage via endogenous topoisomerase poisoning in cells with hyperactive polyamine transport mechanisms. A library of novel polyamine compounds of this sort has been synthesized (and others are being constantly added). In this SBIR, the company will rigorously evaluate these novel compounds for topoisomerase targeting efficacy in vivo using defined model cells lines and in vitro using purified enzymes. This strategy for rational polyamine-topoisomerase drug design will reveal the most effective agents for cancer cell killing while minimizing damage to normal cells. PUBLIC HEALTH RELEVANCE: The development of targeted cancer therapies would be a clear advance in the treatment of cancer. Since cancer costs in the U.S. were nearly 1.4 million lives and $210 billion in 2005, it makes both medical and economic sense to invest in new pharmaceutical technologies. Smart drugs, which can selectively target and kill cancers, would begin to address this important public health issue.

描述（由申请人提供）：靶向拓扑异构酶作用的药物是有效的抗癌药物，其中一些已获得FDA批准。抗拓扑异构酶治疗是基于颠覆内源性拓扑异构酶成基因毒性，DNA损伤剂。这类药物的一个重要问题是对正常细胞的附带损害。由于所有有核体细胞都保留一定水平的拓扑异构酶活性（I型和/或II型），除非能够制定新的策略来减少不良副作用，否则正常健康组织中DNA损伤的负面结果是不可避免的。在这次SBIR中，企业赞助商（TopoGEN, Inc.）提出了一种使用“智能制药”药物设计的组合策略。强效拓扑异构酶毒素可与多胺（例如精胺）偶联，癌细胞根据细胞生长对外源多胺的需求增加而优先处理多胺。有证据表明，新型抗拓扑异构酶/多胺偶联物通过内源性拓扑异构酶中毒在具有多胺运输机制的细胞中诱导优先DNA损伤。这类新型多胺化合物的文库已经被合成（其他的还在不断添加）。在本次SBIR中，该公司将严格评估这些新化合物的拓扑异构酶靶向效力，在体内使用确定的模型细胞系，在体外使用纯化酶。这种合理的多胺拓扑异构酶药物设计策略将揭示最有效的杀死癌细胞的药物，同时最大限度地减少对正常细胞的损害。公共卫生相关性：癌症靶向治疗的发展将是癌症治疗的一个明显进步。2005年，美国因癌症而死亡的人数接近140万人，耗资2100亿美元，因此，投资新的制药技术在医学和经济上都是有意义的。聪明的药物，可以选择性地靶向和杀死癌症，将开始解决这一重要的公共卫生问题。