Oncology smart screening of combinatorial libraries

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。分别是结肠、肺、乳腺、前列腺和卵巢肿瘤。这些肿瘤加起来占人类癌症的70%以上。癌症是美国人死亡的主要原因：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光、放射、生物治疗和化疗；这些疗法在很大程度上对主要肿瘤无效。我们迫切需要发现有效和有选择性的抗肿瘤药物，但由于我们对癌症缺乏了解，这项研究受到严重限制。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/或过程在肿瘤而不是正常组织中是独特的或存在于不同水平。诺华肿瘤研究项目（ORP）采用的初级和次级筛选针对的是涉及信号转导、肿瘤抑制、转录因子和细胞周期的潜在重要蛋白靶点。在大多数常见肿瘤中，这些蛋白质的基因单独或以各种组合形式发生突变或缺失。这种方法不同于更传统的“基于细胞毒性”的癌症药物发现计划。在一级和二级筛选中发现的活性化合物将根据为每个目标建立的流程图进一步检查。然后，具有所需特征的化合物将在裸鼠体内作为异种移植物对人类肿瘤生长进行体内评估，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药物类别提供了丰富的来源，但它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无法实现的方式进一步探索系列中的SARs。通过这两种替代方法产生的化合物混合物可以进行评估，根据初级分析活性进行分馏，并使用天然产物混合物的既定方法分离和鉴定纯化合物。高度复杂独特的“天然产物样”分子文库的创建，潜在相关靶蛋白的广泛数量和相关的高通量筛选能力以及精心设计的二次和体内评估为癌症药物的发现和开发提供了有效的框架。

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.