Anticancer Agents from Plant- and Lichen-Associated Fungi of the Sonoran Desert

描述(申请人提供)：天然产品为人类健康做出了巨大贡献。从天然来源寻找新的先导化合物仍然是现代抗癌药物发现的关键因素。我们的长期目标是从索诺兰沙漠的植物和地衣相关真菌中发现通过新机制发挥作用的抗癌药物，从而为我们的假设提供进一步支持，即生活在这个独特环境中的生物相互关联地形成一种相对未被探索的有效生物活性化合物，以调节它们的相互作用并提高它们的生存能力。这个跨学科和跨机构项目的具体目标是：1.扩大我们独特的索诺兰沙漠植物和地衣相关真菌的生物资源，优化500个精选真菌菌株的生物合成潜力，并准备2,500个提取物用于评估；2.使用基于细胞的生物和分子方法筛选抗癌活性提取物，包括：(A)在我们之前的赠款期间建立的、最近经过修改的检测能够热休克诱导和抑制热休克诱导的化合物，随后进行与Hsp90直接相互作用的分析，包括利用热休克诱导试验分离的化合物的荧光素酶复性和结合分析；(C)在亚细胞毒性浓度下检测细胞运动抑制物，以及(D)基于5个前哨癌细胞系的抑制增殖/存活的常规染料还原试验，以避免发现一般的细胞毒剂；3.去复制活性提取物，每年大规模培养多达5个有希望的真菌菌株，并对其提取物进行生物测定指导的分离，以分离和表征生物活性化合物；以及4.根据最有希望的化合物的活性、结构新颖性和效力，利用基因组和蛋白质组方法确定其分子作用机制。我们期待最有趣的化合物将成为进一步优化开发具有独特作用机制的新型抗癌药物的先导。然而，在更基础的科学层面上，我们提出的创新的化学生物学方法应该有助于定义以下机制：(A)Hsp90等伴侣促进肿瘤发生，以及(B)小分子抑制参与侵袭和转移的癌细胞迁移，从而增强我们预防和治疗癌症的整体能力，从而对公众健康产生重大影响。与公共健康相关：该项目计划从迄今尚未开发的自然来源中发现通过新机制发挥作用的抗癌药物，其结果将导致我们预防和治疗癌症的整体能力增强，从而对公共健康产生重大影响。

DESCRIPTION (provided by applicant): Natural products have made enormous contributions to human health. The search for new lead compounds from natural sources continues to be a crucial element in modern anticancer drug discovery. Our long-term goal is to discover anticancer drugs that act by novel mechanisms from plant- and lichen-associated fungi of the Sonoran desert, thereby providing further support for our hypothesis that organisms living in association with one another in this unique environment elaborate a relatively unexplored repertoire of potent bioactive compounds with which to mediate their interactions and enhance their survival. The specific aims of this interdisciplinary and inter-institutional project are to: 1. expand our unique bio-resource of Sonoran desert plant- and lichen-associated fungi and optimize biosynthetic potential of 500 selected fungal strains and prepare 2,500 extracts for evaluation; 2. screen extracts for anticancer activity using cell-based biological and molecular approaches including: (a) an assay established during our previous grant period and recently modified to detect compounds capable of heat shock induction and inhibition of heat shock induction, followed by assays for direct interaction with Hsp90 including luciferase-refolding and binding assays for compounds isolated using the heat shock induction assay; (c) an assay for inhibitors of cell motility at sub-cytotoxic concentrations, and (d) a conventional dye reduction assay for inhibition of proliferation/survival based on five sentinel cancer cell lines to avoid the discovery of general cytotoxic agents; 3. dereplicate active extracts, culture on large-scale up to five promising fungal strains per year and subject their extracts to bioassay-guided fractionation to isolate and characterize bioactive compounds; and 4. define molecular mechanisms of action using genomic and proteomic approaches for the most promising compounds based on their activity, structural novelty, and potency. We expect that the most interesting compounds will serve as leads for further optimization in the development of novel anticancer agents with unique mechanisms of action. At a more basic scientific level, however, the innovative chemical biology approach we propose should help define the mechanisms by which (a) chaperones such as Hsp90 facilitate oncogenesis, and (b) small-molecules inhibit cancer cell migration involved in invasion and metastasis, leading to enhancement of our overall ability to prevent and cure cancers, and therefore have a great impact on public health. PUBLIC HEALTH RELEVANCE: This project proposes to discover anticancer drugs that act by novel mechanisms from hitherto unexploited natural sources, the outcome of which will lead to enhancement of our overall ability to prevent and cure cancers, and therefore have a great impact on public health.