Diversifying Natural Products via Combinatorial Biosynthesis Methods

在美国，癌症导致每4例死亡中就有1例死亡，优化现有的癌症治疗方案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，临床上有用的。天然产物 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 各种办法面临许多问题和挑战。作为UW的组合生物合成组件， NCDDG计划，我们建议产生一个精心挑选的一组有前途的自然 通过对微生物来源的生物合成途径进行遗传操作，我们的假设是： (1)组合生物合成方法在已证实的抗癌药物生物合成机制中的应用 药物将导致产生具有改善的治疗指数的新型类似物;（2） 组合生物合成方法是一种具有抗肿瘤活性的天然产物的生物合成机制 活性但未解决的作用模式将产生给定分子支架的文库， 新靶点的识别，并导致发现新类别的抗癌药物;（3） 用癌症靶向肽（CTP）和/或肿瘤特异性肽工程化天然产物载体蛋白 用于前药设计的活化位点将使得天然产物药物能够递送至特定的癌症 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 生物合成途径已经在我们的抗癌药物实验室中得到了表征， 的发现该提案的具体目标是：（1）工程和生产天然的新类似物 具有已知作用模式的产品抗癌药物，例如烯二炔C-1027，新制癌素， maduropetin、加利车霉素、动力霉素、来那霉素、海达霉素和瑞贝卡霉素;（2）工程化和 具有有希望的抗肿瘤活性但未解决的抗肿瘤模式的天然产物的新类似物的生产 作用如偏头痛抑制素、dorrigocin、lactimidomycin、互变霉素、互变霉素和fredericamycin;和（3） 工程化和生产含CTP的色蛋白，如C-1027和奈替西司他丁， 组织蛋白酶D和基质-金属蛋白酶-2特异性前药如博来霉素和丝裂霉素C。的 这些研究的结果将导致抗癌药物发现的新靶点的鉴定， 开发全新的、临床上有用的抗癌药物。

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.