Anti-Cancer Drug Design Targeting Human Topoisomerase I

描述（申请人提供）：人拓扑异构酶I（topo I）是唯一的 喜树碱（CPT）和其它“拓扑异构酶I毒物”细胞内靶向， 它们是迄今为止发现的最有前途的抗癌药物之一。翡翠 BioStructures，Inc.成功完成了SBIR第一阶段研究计划 试图阐明人类的X射线晶体结构 拓扑异构酶I与一种或另一种CPT类似物复合。我们现在寻求第二阶段SBIR 基金进行基于结构的药物设计周期，使用我们的2.0 拓扑替康与人拓扑异构体I-DNA结合的埃结构信息 共价复合物我们将采用标准的计算方法来制定一个 三维定量构效关系模型 喜树碱类化合物的研究将对3D-QSAR模型进行验证， 用另外的喜树碱类似物的X射线晶体结构扩展。 现有化学品数据库和世界毒品索引将 通过计算询问适合托泊替康结合的配体 Topo I-DNA结合位点的口袋。3D-QSAR信息将被合并 利用预测的配体结合信息和化学直觉来设计 具有增强的制剂活性的完全新颖的喜树碱类似物 性质（完全E环稳定性，有效的脂质体包封，容易 与聚乙二醇缀合）。新的喜树碱类似物将是 合成、纯化并测试它们对topo I的抑制作用 活性，它们对使用固定化拓扑异构酶I-DNA的共价复合物的亲和力 共价复合物及其对人肿瘤细胞系的细胞毒性。最 有希望的化合物将被检测其在阻止人类肿瘤中的功效 在小鼠异种移植模型中的生长。 拟定商业应用： 不可用

DESCRIPTION (provided by applicant): Human topoisomerase I (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. Emerald BioStructures, Inc. has successfully completed a Phase I SBIR research program that sought to elucidate the X-ray crystal structure of human topo I in complex with one or another CPT-analogue. We now seek Phase 2 SBIR funds to conduct an integrated structure-based drug design cycle using our 2.0 angstrom structural information of Topotecan bound to the human topo I-DNA covalent complex. We will employ standard computational methods to formulate a three-dimensional quantitative structure-activity relationship (3D-QSAR) model for the camptothecin-type compounds. The 3D-QSAR model will be validated and extended with X-ray crystal structures of additional camptothecin analogues. The Available Chemicals Database and the World Drug Index will be computationally interrogated for ligands that fit into the Topotecan binding pocket of the topo I-DNA binding site. The 3D-QSAR information will be combined with the predicted ligand binding information and chemical intuition to design completely novel camptothecin analogues that have enhanced formulative properties (complete E-ring stability, efficient liposome encapsulation, facile conjugation to polyethylene glycol). The novel camptothecin analogues will be synthesized, purified, and tested for their inhibitory effects on topo I activity, their affinity for the covalent complex using immobilized topo I-DNA covalent complexes, and their cytotoxicity to human tumor cell lines. The most promising compounds will be examined for their efficacy in stopping human tumor growth in the mouse xenotransplant model. PROPOSED COMMERCIAL APPLICATION: Not available