DEVELOPMENT OF NOVEL DRUGS FOR PH1 POSITIVE LEUKEMIA

开发治疗 PH1 阳性白血病的新药

• 批准号: 3549894
• 负责人: J FOULKES
• 金额: $ 94.33万
• 依托单位: OSI PHARMACEUTICALS, INC.
• 依托单位国家: 美国
• 财政年份: 1992
• 资助国家: 美国
• 起止时间: 1992-09-30 至 1995-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3549894
• 关键词: acute lymphocytic leukemia; antineoplastics; chromosome translocation; chronic myelogenous leukemia; cooperative study; drug screening /evaluation

The Ph1 chromosome arises as a result of a translocation between chromosomes 9 and 22, which fuses two genes, termed bcr and abl. The involvement of bcr-abl fusion proteins in Ph1 positive chronic myelogenous leukemia (CML) and acute lymphoblastic leukemia (ALL) represents the best mechanism of action model in human cancer. This group has been formed to develop drugs which specifically target the bcr-abl fusion as a means of treating Ph1 positive leukemia patients. The groups strategy involves very high throughput drug screening technology, facilitated by recent advances which make it possible to rapidly evaluate hundreds of thousands of samples. Oncogene Science has developed the leading technology in this area. Our experience over the last seven years has clearly demonstrated that running several distinct screens, each capable of identifying unique leads, is the best way to generate high quality leads. Dr. Goddard's group will run two screens (one in vitro, one in vivo) which target the activated tyrosine kinase activity of the bcr-abl fusion protein and one which seeks compounds which transcriptionally inhibit expression of the fusion gene. Dr. Katz heads a group which will supply 80,000 fungal fermentation extracts to screen. Screens will also evaluate 20,000 compounds from Oncogene Science's chemical library. Leads from the screens will be prioritized on the basis of potency and selectivity and then analoged by Dr. J. Slack's SAR chemistry team. Following further analysis in a variety of hematological cell culture models by Dr. Borzillo's group, the best leads will proceed into animal models. One group, headed by Dr. J. Groffen, will test leads in a murine ALL model, while Dr. Van Etten's group will test leads in a CML-like model. We believe this NCDDG represents a powerful team for the generation of novel, mechanism of action based drug candidates for Ph1 positive leukemia.

pH1染色体是由于 染色体9和22，融合了两个基因，称为BCR和ABL。 这 BCR-ABL融合蛋白参与PH1阳性慢性骨髓 白血病（CML）和急性淋巴细胞白血病（ALL）代表最好的 人类癌症作用模型的机理。 这个小组已成立 开发专门针对BCR-ABL融合的药物作为 治疗PH1阳性白血病患者。 小组策略涉及非常 高通量药物筛查技术，最新进展促进 这使得可以快速评估成千上万 样品。 癌基科学在这方面发展了领先的技术 区域。 我们过去七年中的经验清楚地证明了 运行几个不同的屏幕，每个屏幕都能识别独特的屏幕 铅是产生高质量线索的最佳方法。 戈达德博士的小组 将运行两个靶向激活的屏幕（一个在体外，一个体内） BCR-ABL融合蛋白的酪氨酸激酶活性和寻求的酪氨酸活性 转录抑制融合基因表达的化合物。 Katz博士负责一个小组，该小组将提供80,000个真菌发酵 提取到屏幕。 屏幕还将评估20,000种化合物 Oncogene Science的化学图书馆。 屏幕上的线索将是 根据效力和选择性优先考虑 J. Slack博士的SAR化学团队。 在进行进一步分析 Borzillo博士小组的各种血液学细胞培养模型， 最好的铅将进入动物模型。 一组由J.博士领导。 格罗佛（Groffen），将在所有模型中测试铅，而范·埃滕（Van Etten）的小组 将在类似CML的模型中测试引线。 我们相信这个ncddg代表 强大的团队，以创造基于动作的药物机制 PH1阳性白血病的候选者。