ANTICANCER COMPOUNDS DESIGNED TO POISON TOPOISOMERASE I

人类拓扑异构酶I （topi）是喜树碱（CPT）和其他“拓扑异构酶I”的唯一细胞内靶点，其中一些是迄今为止发现的最有希望的抗癌药物。Emerald BioStructures, Inc.正积极参与一项I期SBIR研究，旨在阐明人类topo I与喜树碱（CPT）及其衍生物复合物的x射线晶体结构。我们现在寻求“灵活的”SBIR基金，以扩大我们基于结构的方法设计新的抗癌化合物的范围。我们建议确定人类topo I与新型吲哚咔唑和其他非cpt毒素配合物的x射线晶体结构，这些毒素已显示出有希望的抗癌活性。从这一努力中获得的信息将使智能II期设计和合成专有抗癌化合物成为可能，这些化合物包含了来自各种拓扑I毒物的重要结构特征。我们还打算研究人类topo I抗cpt突变体的x射线晶体结构，以及人类topo I和SV40大t抗原之间形成的复合物，SV40大t抗原是一种已被证明与topo I相互作用的解旋酶（概括拓扑异构酶生物学中的一个共同主题）。这些额外的结构确定将为耐药性的分子机制和其他蛋白质在定义药物敏感性方面的作用提供见解，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：这项拟议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，这些化合物可能会用于减轻美国每年140多万被诊断为癌症的人的痛苦，这些人在现有治疗上的花费估计为350亿美元。第一阶段的成功有望为正在开发用于治疗人类癌症的topo I毒药的大型制药公司提供多个合作研究合同的机会。此外，从人体topo I-毒药复合物的x射线结构测定中获得的信息将为几种全新topo I毒药的患者应用奠定基础。

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.