Diversifying Natural Products via Combinatorial Biosynthesis Methods

在美国，每4人中就有1人死于癌症，优化可获得性是一个关键的研究目标 抗癌药物，并发现和开发从根本上新的、临床有用的药物。天然产品有 作为抗癌药物来源的良好记录，但传统的天然产物药物发现 这些方法面临许多问题和挑战。作为UW的组合生物合成成分 NCDDG计划，我们建议制作一套精心挑选的自然小文库 微生物来源的产物通过对其生物合成途径的遗传操作而产生的产物。我们的假设是： (1)组合生物合成方法在已被证实的抗癌生物合成机械中的应用 药物将产生新的类似物，改善治疗指数； 具有抗肿瘤前景的天然产物生物合成机械的组合生物合成方法 活动但未解决的作用模式将生成给定分子支架的文库，促进 新靶点的确定和抗癌药物新类别的发现； 肿瘤靶向多肽和/或肿瘤特异性天然产物载体蛋白的工程研究 前药设计的激活部位将使天然产物药物能够输送到特定的癌症 细胞。该项目的长期目标是将组合生物合成方法应用于各种 我们的实验室已经确定了抗癌药物的生物合成途径 发现号。这项建议的具体目标是：(1)设计和生产新型的天然类似物 生产已知作用模式的抗癌药物，如烯二炔类C-1027，新卡西宁， 马杜菌素、卡利卡米星、动力素、雷诺霉素、海达霉素和瑞贝卡霉素；(2)工程和 具有良好抗肿瘤活性但尚未解决的模式的天然产物的新类似物的生产 作用如米曲他汀、多利古霉素、拉米霉素、直霉素、直霉素和弗雷德霉素；以及(3) C-1027、Neicarzinostatin等含CTP显色蛋白的工程及生产 组织蛋白酶D和基质金属蛋白酶-2特异性前药，如博莱霉素和丝裂霉素C。 这些研究的结果将导致确定抗癌药物发现的新靶点，并 开发根本性的、临床有用的抗癌药物。

Cancer causes 1 of every 4 deaths in the US, and it is a critical research goal to optimize available anticancer drugs and discover and develop fundamentally new, clinically useful ones. Natural products have an excellent track record as sources of anticancer drugs but traditional natural product drug discovery approaches face many problems and challenges. As the combinatorial biosynthesis component of the UW NCDDG program, we propose to produce small libraries of a carefully selected set of promising natural product leads of micribial origin by genetic manipulations of their biosynthetic pathways. Our hypotheses are: (1) application of combinatorial biosynthetic methods to the biosynthetic machinery of proven anticancer drugs will result in the production of novel analogs with an improved therapeutic index; (2) application of combinatorial biosynthetic methods to biosynthetic machinery of natural products with promising antitumor activities but unresolved modes of action will generate libraries of the given molecular scaffold, facilitating the identification of novel targets and leading to the discovery of new classes of anticancer drugs; (3) engineering of natural product carrier proteins with cancer targeting peptides (CTPs) and/or tumor-specific activation sites for prodrug design will enable the delivery of the natural product drugs to specific cancer cells. The long-term goal of this project is to apply combinatorial biosynthetic methods to the various biosynthetic pathways that have already been characterized in our laboratories for anticancer drug discovery. The specific aims for this proposal are: (1) engineering and production of novel analogs of natural product anticancer drugs with known modes of action such as the enediynes C-1027, neocarzinostatin, maduropetin, calicheamicin, dynamicin, leinamycin, hedamycin, and rebeccamycin; (2) engineering and production of novel analogs of natural products with promising antitumor activities but unresolved modes of action such as migrastatin, dorrigocin, lactimidomycin, tautomycin, tautomycetin, and fredericamycin; and (3) engineering and production of CTP-containing chromoproteins such as C-1027 and neicarzinostatin and of cathepsin D and matrix-metalloprotease-2 specific prodrugs such as bleomycin and mitomycin C. The outcomes of these studies will lead to the identification of novel targets for anticancer drug discovery and to the development of fundamentally new, clinically useful anticancer drugs.