ANTICANCER DRUG DESIGN TARGETING HUMAN TOPOISOMERASE I

人拓扑异构酶I（topo I）是唯一的细胞内靶点， 喜树碱（CPT）和其他“拓扑I毒物”，其中一些是 最有前途的抗癌药物但缺乏 药物结合的高分辨率结构信息是一个主要的 设计新型拓扑一型毒药的绊脚石我们准备开发 用于结晶人拓扑异构酶I与一种或多种蛋白质的复合物的方案， 另一种拓扑异构酶I这些化合物结合到瞬时 共价拓扑结构I-DNA复合物，在那里它们阻碍了 催化并将酶转化为DNA损伤剂。 我们 结晶试验将进行一系列创新的 永久捕获共价复合物的硅化物衬底。所有 试验的理化参数及其结果将 使用专有的Crystal Monitor（TM）在关系数据库中捕获 软件对捕获信息的分析将加速 一种或多种三元化合物的X射线衍射质量晶体的制备 人拓扑异构酶1-DNA-药物复合物。这项奋进的成功将提供 一个原子分辨率的观点如何拓扑I毒药相互作用， 目标，并将使Emerald BioStructures，Inc.应用结构- 在设计全新的抗癌化合物中的基于方法， 靶向人类拓扑I 拟议的商业应用： 这项研究具有巨大的商业和人道主义价值， 它将使合理设计新的抗癌化合物成为可能， 有一天可以用来减轻140多万人的痛苦， 在美国，每年都有100多人被诊断出患有癌症， 估计有350亿美元用于治疗。 第一阶段的成功是 预计将为合作研究提供多种机会 与大型制药公司的合同， 用于治疗人类癌症的拓扑异构酶I毒药。此外该 从高分辨率的人体拓扑图中获得的信息- 毒药复合物将成为专利申请的基础， Emerald BioStructures，Inc.将寻求确保所有权地位 对于某些新的化合物类别， 是有效的局部毒药。

Human topoisomerase l (topo I) 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. However, the lack of high resolution structural information on drug binding is a major stumbling block in the design of new topo I poisons. We intend to develop protocols for the crystallization of human topo I in complex with one or another of the topo I poisons. These compounds bind to the transient covalent topo I-DNA complex, where they impede the relegation phase of catalysis and convert the enzyme into a DNA damaging agent. Our crystallization trials will be conducted with a series of innovative suicide substrates that permanently trap the covalent complex. All physiochemical parameters of the trials and their results will be captured in a relational database using proprietary Crystal Monitor(TM) software. Analysis of the captured information will accelerate the production of x-ray diffraction quality crystals of one or more ternary human topo 1-DNA-drug complexes. Success in this endeavor would provide an atomic resolution view of how topo I poisons interact with their target, and will enable Emerald BioStructures, Inc. to apply structure- based methods in the design of totally novel anticancer compounds that target human topo I. PROPOSED COMMERCIAL APPLICATIONS: 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 who are diagnosed with cancer each year in the US, 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 the larger pharmaceutical companies that are developing topo I poisons for the treatment of human cancers. In addition, the information gained from a high resolution picture of the human topo I- poison complex would form the basis for a patent application wherein Emerald BioStructures, Inc. would seek to secure an ownership position with respect to certain novel classes of compounds that are predicted to be effective topo I poisons.