Oncology smart screening of combinatorial libraries

肿瘤学智能筛选组合文库

• 批准号: 6222361
• 负责人: KENNETH W BLAIR
• 金额: --
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-09-23 至 2004-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6222361
• 关键词: antineoplastics; athymic mouse; biological products; chemical structure function; combinatorial chemistry; drug discovery /isolation; drug screening /evaluation; genetic library; neoplasm /cancer transplantation; neoplastic growth

The long-term objective of this collaborative research is to discover novel anti-cancer drugs that are useful against the major types of cancer. These are the colon, lung, breast, prostate and ovarian tumors. Together, these tumors comprise over 70% of human cancers. Cancer is a major cause of death in the USA: over 536,000 Americans due from the disease annually. At present, cancer is treated by surgery, X-ray, radiation, biological therapy and chemotherapy; these therapies are largely ineffective against the major tumors. There is a critical need to discover effective and selective anti-tumor drugs, but this research is severely limited by our lack of understanding of cancer. Our work focuses on the development of anti- tumor drugs that affect some of the more recently discovered targets and/or processes that are unique or present at different levels in tumors rather than normal tissue. The primary and secondary screens employed by the Oncology Research Program (ORP) at Novartis are aimed at potentially important protein targets involved in signal transduction, tumor suppression, transcription factors and the cell cycle. Singly or in various combinations, the genes for each of these proteins are mutated or deleted in the majority of common tumors. This approach is different from the more traditional "cytotoxicity- based" cancer drug discovery programs. Compounds found to be active in the primary and secondary screens will be further examined according to Flow Charts established for each target. Compounds with the desired profile will then be evaluated in vivo against human tumors growing as xenografts in nude mice and following successful development enter into human clinical trials. The diversity of natural products has provided a rich source of novel anti- tumor agent classes, but it still appears to be under-utilized. Combinatorial biosynthesis and combinatorial chemistry technologies may provide the means to produce additional compounds related to interesting natural products and to further explore SARs within series in ways not possible with traditional methods of isolation and semi- or total synthesis. Mixtures of compounds produced by these two alternative methods can be evaluated, fractionated according to primary assay activity, and pure compounds isolated and identified using established methods for natural product mixtures. The creation of libraries of highly complex unique"natural product-like" molecules, the broad number of potentially relevant target proteins and associated high throughput screening capacity and well-designed secondary and in vivo evaluations provide an effective framework for cancer drug discovery and development.

这项合作研究的长期目标是发现对主要类型癌症有用的新型抗癌药物。这些是结肠、肺、乳腺、前列腺和卵巢肿瘤。这些肿瘤占人类癌症的70%以上。癌症是美国的主要死亡原因：每年有超过536，000名美国人死于这种疾病。目前，癌症的治疗方法有手术、X射线、放射、生物疗法和化学疗法;这些疗法对主要肿瘤基本无效。目前迫切需要发现有效和选择性的抗肿瘤药物，但由于我们对癌症缺乏了解，这一研究受到严重限制。我们的工作重点是开发抗肿瘤药物，这些药物影响一些最近发现的靶点和/或过程，这些靶点和/或过程是独特的或存在于肿瘤而不是正常组织中的不同水平。诺华公司肿瘤研究计划（ORP）采用的初级和二级筛选针对的是参与信号转导、肿瘤抑制、转录因子和细胞周期的潜在重要蛋白质靶点。在大多数常见肿瘤中，这些蛋白质中的每一种的基因单独或以各种组合发生突变或缺失。这种方法与更传统的“基于细胞毒性”的癌症药物发现计划不同。将根据为每个靶标建立的流程图进一步检查在初级和二级筛选中发现具有活性的化合物。然后，将针对在裸鼠中作为异种移植物生长的人肿瘤在体内评估具有所需特征的化合物，并在成功开发后进入人体临床试验。天然产物的多样性为新型抗肿瘤剂类别提供了丰富的来源，但似乎仍未得到充分利用。组合生物合成和组合化学技术可以提供生产与感兴趣的天然产物相关的其他化合物的手段，并以传统的分离和半合成或全合成方法不可能的方式进一步探索系列内的SAR。可以评估通过这两种替代方法产生的化合物的混合物，根据初步测定活性进行分级，并使用天然产物混合物的既定方法分离和鉴定纯化合物。创建高度复杂的独特的“天然产物样”分子库、大量潜在相关的靶蛋白和相关的高通量筛选能力以及精心设计的二级和体内评价为癌症药物发现和开发提供了有效的框架。