Isolation Chemistry of Filamentous Fungi and Biological Evaluation

项目3包括北卡罗来纳大学格林斯伯勒分校(化学 通过Nicholas Oberlie实验室)、MyCosynthetix，Inc.(真菌学)和哥伦比亚大学(生物学) 通过布伦特·斯托克韦尔实验室进行评估)。假设抗癌药物具有新的结构 将从丝状真菌中获得。因此，项目3的目标是发现结构多样化的 以及有利于药物开发的规模的生物活性化合物。要做到这一点，三个具体 目标可以概括为： 具体目标1：从Mycoynthetix文库中选择和培养真菌，重点是不寻常的培养和 那些可能会产生有希望的线索的人。 特定目的2.生物活性先导化合物的提取、分离和结构鉴定。 特定目标3.检测致癌RAS选择性致死性和新的细胞死亡机制的样本 基因工程的肿瘤细胞。 根据最初申请审查员的有益建议，对项目3进行了修订。三位一体 旨在以迭代的方式为项目3工作，以抗癌领导，在真菌学方面具有独特的技能(目标1) 为评估生物活性的天然产物化学(目标2)提供样本(目标3)。 重要的是，后一个目标将集中在与致癌RAS合成致命的化合物上。房协 癌蛋白(K-RAS、H-RAS、N-RAS)在癌症生物学中具有极其重要的作用。他们是被发现的 30多年前，但一直抵制直接以小分子为靶标。因此，尽管事实是 KRAS基因在~20%的肿瘤中发生突变，而在95%的胰腺癌中，没有治疗方法 用于治疗突变的KRAS肿瘤。在肿瘤细胞中显示出增强效力和杀伤力的化合物 致癌的RAS可能表现出更高的治疗指数，并揭示靶向的机制 具有三个RAS基因(HRAS、NRAS和KRAS)突变的肿瘤。 该计划的资源将用于推动临床前开发的最佳线索。 除了其他项目和核心的技能，这将包括与我们的企业合作伙伴的密切互动， 卫材公司(马萨诸塞州安多弗)，他在开发抗癌天然产品方面有着成功的记录。 这部分计划项目的主要目的是发现新的癌症化疗药物。 来自丝状真菌的培养。为此，我们小组将进行化学和生物研究 与该项目的其他组成部分协调一致。

Project 3 comprises a collaborative effort between the University of North Carolina at Greensboro (chemistry via the Nicholas Oberlies Lab), Mycosynthetix, Inc. (mycology), and Columbia University (biological evaluation via the Brent Stockwell Lab). It is hypothesized that anticancer drug leads with novel structures will be obtained from filamentous fungi. Hence, the goal of Project 3 is the discovery of structurally diverse and biologically active compounds on a scale that facilitates drug development. To do so, the three specific aims can be summarized as: Specific Aim 1: Select and culture fungi from the Mycosynthetix library, focusing on unusual cultures and those likely to produce promising leads. Specific Aim 2. Dereplication, Isolation and structure elucidation of bioactive lead compounds. Specific Aim 3. Test samples for oncogenic-Ras selective lethality and novel cell death mechanisms using engineered tumor cells. Project 3 has been revised per the helpful suggestions of the reviewers of the initial application. The three aims for Project 3 work in an iterative manner toward anticancer leads, with unique skills in mycology (Aim 1) providing samples for natural products chemistry (Aim 2) that are evaluated for biological activity (Aim 3). Importantly, this latter aim will focus on compounds that are synthetic lethal with oncogenic Ras. The Ras oncoproteins (K-Ras, H-Ras, N-Ras) are of paramount importance in cancer biology. They were discovered over 30 years ago, but have been resistant to direct targeting with small molecules. Thus, despite the fact that the KRAS gene is mutated in ~20% of all tumors, and >95% of pancreatic cancers, there is no therapy for treating mutant KRAS tumors. Compounds that show increased potency and lethality in tumor cells with oncogenic Ras are likely to exhibit an increased therapeutic index, and to reveal mechanisms for targeting tumors harboring mutations in the three Ras genes (HRAS, NRAS and KRAS). The resources of the Program will be utilized for pushing the best leads towards preclinical development. Besides the skills of the other Projects and Cores, this will include close interaction with our corporate partner, Eisai Inc (Andover, MA), who has a successful track record of developing anticancer natural products. The primary purpose of this part of the program project is to discover new cancer chemotherapeutic agents from cultures of filamentous fungi. In order to do this, our group will perform chemical and biological studies in a coordinated manner with the other components of this project.