Isolation Chemistry of Filamentous Fungi and Biological Evaluation

项目3包括格林斯伯勒的北卡罗来纳州大学（化学 通过Nicholas Oberlies Lab），Mycosynthetix，Inc.（真菌学）和哥伦比亚大学（生物 通过布伦特斯托克韦尔实验室评价）。据推测，抗癌药物导致新的结构， 将从丝状真菌获得。因此，项目3的目标是发现结构多样的 和生物活性化合物的规模，以促进药物开发。为此，三个具体 其目标可概括为： 具体目标1：从Mycosynthetix文库中选择和培养真菌，重点关注不寻常的培养物， 那些可能产生有希望的线索。 具体目标2。生物活性先导化合物的去复制、分离和结构鉴定。 具体目标3。用于致癌性Ras选择性致死性和新型细胞死亡机制的测试样品， 工程肿瘤细胞 项目3已根据初步申请的审查人员的有益建议进行了修订。三 项目3的目标是以迭代的方式朝着抗癌方向努力，并具有真菌学方面的独特技能（目标1） 为天然产物化学（目标2）提供样品，并对其进行生物活性评价（目标3）。 重要的是，后一个目标将集中在与致癌Ras合成致死的化合物上。的Ras 癌蛋白（K-Ras、H-Ras、N-Ras）在癌症生物学中是极其重要的。他们被发现 但对小分子的直接靶向具有抗性。因此，尽管 KRAS基因在约20%的肿瘤和>95%的胰腺癌中发生突变， 用于治疗突变型KRAS肿瘤。在肿瘤细胞中显示出增加的效力和致死性的化合物， 致癌Ras可能表现出增加的治疗指数，并揭示靶向的机制， 在三种Ras基因（HRAS、NRAS和KRAS）中携带突变的肿瘤。 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密切互动， 该公司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 从丝状真菌的培养物中分离出来。为了做到这一点，我们的小组将进行化学和生物学研究 与本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.