ANTICANCER COMPOUNDS DESIGNED TO POISON TOPOISOMERASE I

人拓扑异构酶I（topoI）是喜树碱（CPT）和其他“topo I毒物”的唯一细胞内靶点，其中一些是迄今为止鉴定的最有前途的抗癌药物。Emerald BioStructures，Inc.积极参与I期SBIR研究，该研究试图阐明与喜树碱（CPT）及其衍生物复合的人拓扑异构酶I的X射线晶体结构。我们现在寻求“灵活”SBIR基金，以扩大我们设计新抗癌化合物的结构为基础的方法的范围。我们建议，以确定X-射线晶体结构的人拓扑异构酶I在复杂的新的吲哚并咔唑和其他非CPT毒药，已被证明有前途的抗癌活性。从这一奋进中获得的信息将使智能第二阶段设计和合成的专有抗癌化合物，纳入重要的结构特征，从各种拓扑I毒药。我们还打算追求CPT耐药突变体的X射线晶体结构的人拓扑异构酶I，以及复合物之间形成的人拓扑异构酶I和SV 40大T-抗原，解旋酶已被证明与拓扑异构酶I相互作用（概括拓扑异构酶生物学中的一个共同主题）。这些额外的结构测定将提供对耐药性的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。拟定商业应用：这项拟议中的研究具有巨大的商业和人道主义价值，因为它将使新的抗癌化合物的合理设计成为可能，有朝一日可能用于减轻美国每年超过140万被诊断患有癌症的人的痛苦。估计花费了350亿美元用于治疗。第一阶段的成功预计将为与正在开发用于治疗人类癌症的拓扑I毒药的大型制药公司签订合作研究合同提供多种机会。此外，从人类拓扑I-毒物复合物的X-射线结构测定中获得的信息将形成几种患者应用于全新类别的拓扑I毒物的基础。

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.