Molecular Target Focused Discovery of Anticancer Drugs

描述（由申请人提供）：与过去一样，持续研究的目标将是为美国国家癌症研究所加速发现和临床前开发新的和结构独特的抗癌候选药物。重点将继续放在从陆生节肢动物、海洋生物、微生物和植物中分离的小分子抗癌成分，然后进行结构测定、合成和/或结构修饰。将特别强调新的抗肿瘤物质，这些物质要么是基于分子靶生物测定分离出来的，要么是随后显示出这种有效的抗血管生成、癌症血管靶向、微管蛋白和/或各种与癌症相关的激酶（周期蛋白依赖、蛋白激酶C、酪氨酸激酶和端粒酶）特性，以及异常强大的抗肿瘤活性。进一步的研究将重点放在推进auristatins， bryostatin 1， dolastatins以及我们实验室发现的其他药物的扩展和至关重要的临床试验上，例如强大的癌症抗血管生成和血管靶向药物combretastatin （CA4P, CA1P）和其他系列。只有那些从节肢动物、海洋无脊椎动物、海洋和陆生植物、海洋和陆生微生物中确认的活性提取物中获得的线索，才能最大限度地产生具有潜在临床活性的新药。该研究将为DCTD/NCI选择新的抗癌候选药物并加速其临床试验提供重要帮助。总之，拟议的研究将集中于发现和快速开发新的抗癌药物，用于NCI旨在改善人类癌症治疗的项目。公共卫生相关性：未来一年，仅在美国就将有约60万人死于癌症。发现和开发更有效和更有疗效的抗癌药物是全球努力解决这一破坏性健康问题的重要组成部分。该项目的目标是从陆生节肢动物、海洋生物、微生物和植物中发现和开发具有足够抗肿瘤活性的新型小分子，为最终临床治疗人类癌症提供潜力。

DESCRIPTION (provided by applicant): As in the past the very vigorous and sharply focused objective of the continuation research will be the accelerated discovery and preclinical development of new and structurally unique anticancer drug candidates for the U.S. National Cancer Institute. Emphasis will continue to be devoted to small molecule anticancer constituents isolated from terrestrial arthropods, marine organisms, microorganisms and plants followed by structural determinations, syntheses and/or structural modifications. Special emphasis will be placed on new antineoplastic substances either isolated based on molecular target bioassays or subsequently displaying such potent antiangiogenesis, cancer vascular targeting, tubulin and/or various cancer-implicated kinase (cyclin-dependent, protein kinase C, tyrosine kinase and telomerase) properties as well as exceptionally strong antineoplastic activity. Additional emphasis will be placed on further research necessary to advance the expanding and vitally important clinical trials of the auristatins, bryostatin 1, the dolastatins, and others discovered in our laboratory such as the powerful cancer antiangiogenesis and vascular targeting drugs in the combretastatin (CA4P, CA1P) and other series. Only those leads from confirmed active extracts of arthropods, marine invertebrates, marine and terrestrial plants, and marine as well as terrestrial microorganisms that give maximum promise of yielding new drugs with potential clinical activity will be pursued. The proposed continuation research will provide great assistance to the DCTD/NCI in selecting new anticancer drug candidates and speeding their development toward clinical trials. In summary, the proposed research will be sharply aimed at the discovery and very rapid development of new anticancer drugs for the NCI programs directed at improving human cancer treatments. PUBLIC HEALTH RELEVANCE: In the coming year approximately 600,000 people will die of cancer in the United States alone. The discovery and development of more effective and curative anticancer drugs is a vital component in the global effort to address this devastating health problem. The goal of this project is the discovery and development of novel small molecules from terrestrial arthropods, marine organisms, microorganisms, and plants with sufficient antineoplastic activity to offer the potential for ultimate clinical activity against human cancer.