Molecular Target Focused Discovery of Anticancer Drugs

描述(由申请人提供)：与过去一样，继续研究的非常有力和高度集中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、结构独特的抗癌候选药物。重点将继续放在从陆地节肢动物、海洋生物、微生物和植物中分离出的小分子抗癌成分上，然后进行结构确定、合成和/或结构修饰。将特别强调新的抗肿瘤物质，要么是基于分子靶标生物测定分离的，要么是随后表现出如此强大的抗血管生成、肿瘤血管靶向、微管蛋白和/或各种与癌症相关的激酶(细胞周期蛋白依赖性、蛋白激酶C、酪氨酸酶和端粒酶)特性以及非常强的抗肿瘤活性。此外，还将重点放在必要的进一步研究上，以推进扩大的和至关重要的临床试验，如Auristatins、bryostatin 1、Dolastatins和我们实验室发现的其他药物，如强大的抗癌血管生成和血管靶向药物联合试验(CA4P、CA1P)和其他系列。只有从节肢动物、海洋无脊椎动物、海洋和陆地植物以及海洋和陆地微生物的确认活性提取物中获得的线索才会被追查，这些线索最大限度地有望产生具有潜在临床活性的新药。建议的继续研究将为DCTD/NCI选择新的抗癌候选药物和加快其临床试验发展提供极大的帮助。总之，拟议的研究将尖锐地针对NCI项目发现和非常快速地开发新的抗癌药物，旨在改善人类癌症的治疗。与公共卫生相关：未来一年，仅在美国就有大约60万人死于癌症。发现和开发更有效和更有效的抗癌药物是解决这一毁灭性健康问题的全球努力的重要组成部分。该项目的目标是发现和开发来自陆地节肢动物、海洋生物、微生物和植物的新型小分子，这些小分子具有足够的抗肿瘤活性，从而为最终的临床抗癌活性提供潜力。

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.