ANTICANCER COMPOUNDS DESIGNED TO POISON TOPOISOMERASE I

旨在毒害拓扑异构酶 I 的抗癌化合物

• 批准号: 2903492
• 负责人: LANCE J STEWART
• 金额: $ 24.43万
• 依托单位: EMERALD BIOSTRUCTURES
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-07-01 至 2001-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2903492
• 关键词: DNA topoisomerases; X ray crystallography; antineoplastics; camptothecin; carbazoles; chemical structure; chemical synthesis; crystallization; drug design /synthesis /production; tumor antigens

Human topoisomerase I (topoI) is the sole intracellular target of camptothecin (CPT) and other "topo I poisons," some of which are among the most promising anticancer drugs ever identified. Emerald BioStructures, Inc. is actively engaged in a Phase I SBIR study that seeks to elucidate the X-ray crystal structure(s) of human topo I in complex with camptothecin (CPT) and derivatives thereof. We now seek "Flexible" SBIR funds to broaden the scope of our structure-based approach toward designing new anticancer compounds. We propose to determine the X-ray crystal structures of human topo I in complex with novel indolocarbazoles and other non-CPT poisons that have demonstrated promising anticancer activities. The information gained from this endeavor will enable the intelligent Phase II design and synthesis of proprietary anticancer compounds that incorporate important structural features from a variety of topo I poisons. We also intend to pursue the X-ray crystal structures of CPT-resistant mutants of human topo I, as well as the complex formed between human topo I and SV40 Large T-antigen, a helicase that has been shown to interact with topo I (recapitulating a common theme in topoisomerase biology). These additional structure determinations will provide insights into the molecular mechanisms of drug resistance and the roles of other proteins in defining drug sensitivity, an essential component of any modern drug design effort. PROPOSED COMMERCIAL APPLICATION: The proposed research has immense commercial and humanitarian value since it will enable the rational design of new anticancer compounds that might one day be used to relieve the suffering of over 1.4 million people diagnosed with cancer each year in the U.S., and which spend an estimated $35 billion on available treatments. Success in Phase I is expected to provide multiple opportunities for collaborative research contracts with larger pharmaceutical companies that are developing topo I poisons for treatment of human cancers. In addition, the information gained from the X-ray structure determinations of the human topo I- poison complexes would form the basis for several patient applications on totally new classes of topo I poisons.

人拓扑异构酶I（topoi）是Camptothecin（CPT）和其他“ Topo I Poison”的唯一细胞内靶标，其中一些是有史以来最有希望的抗癌药物之一。 Emerald Biostructures，Inc。正在积极参与I期SBIR研究，该研究旨在阐明与camptothecin（CPT）及其衍生物复杂化的人类拓扑I的X射线晶体结构。现在，我们寻求“灵活”的SBIR资金来扩大我们基于结构的方法设计新抗癌化合物的范围。我们建议与新的吲哚吡喃唑和其他表现出有希望的抗癌活性的新型非cpt毒物一起确定人托普I的X射线晶体结构。从这项工作中获得的信息将使智能阶段II期设计和专有抗癌化合物的合成，这些抗癌化合物融合了来自各种Topo I Poison的重要结构特征。我们还打算追求人托普I的CPT耐药突变体的X射线晶体结构，以及人类拓扑I和SV40大型T-抗原之间形成的复合物，这是一种与Topo I相互作用的解旋酶（概括拓扑异构酶生物学中的共同主题）。这些额外的结构确定将提供有关耐药性分子机制以及其他蛋白质在定义药物敏感性中的作用的见解，这是任何现代药物设计工作的重要组成部分。拟议的商业应用：拟议的研究具有巨大的商业和人道主义价值，因为它将能够合理设计新的抗癌化合物，这些化合物可能有一天可以用来减轻美国每年被诊断出癌症的140万人的痛苦，并且花费大约350亿美元上的可用治疗。预计在第一阶段的成功将为与大型制药公司签订的合作研究合同提供多个机会，这些公司正在开发用于治疗人类癌症的Topo I Poison。此外，从人托托毒药络合物的X射线结构确定中获得的信息将构成几种全新的Topo I Poison类别的患者应用的基础。