Random aptamers to probe SCL function in vivo.

现代化疗的目的是对肿瘤细胞发挥最大的作用，同时对正常细胞的副作用最小。我们对癌症分子生物学的理解取得了显着进展，为更成功的靶向癌症治疗提供了可能的途径。癌症特异性蛋白质（称为癌蛋白）之间的几种关键相互作用主要发生在肿瘤细胞中，因此为干预提供了理想的靶点。拟议的项目是通过阻断癌蛋白之间的相互作用来开发一种针对白血病细胞的靶向特异性治疗的模型系统。此外，分离特定蛋白质-蛋白质相互作用的特定阻断剂的能力提供了一个机会，以解开哺乳动物系统中复杂的遗传途径，这是相对棘手的其他分析。使用特异性阻断剂对通路的解剖也可能为识别新的药物靶点提供有用的途径。在寻找特异性抑制剂的过程中，我们选择了涉及一种已知癌蛋白的特定相互作用为目标。将使用遗传选择来鉴定能够阻断这些相互作用并且不干扰涉及癌蛋白的其他相互作用的随机的、受约束的肽序列。该技术允许从含有面包酵母细胞中数百万候选药物先导的文库中选择已知相互作用的特定阻断剂。该程序最适合高通量药物筛选项目。这种方法的有效性，以确定新的肽类药物的线索，将最终建立在体内使用转基因模型的癌蛋白依赖性癌症的小鼠。

Modern chemotherapies are designed to exert maximal effect on tumour cells while having minimal side-effects on normal cells. Remarkable advances in our understanding of the molecular biology of cancer has provided possible avenues for more successful targeted cancer treatments. Several crucial interactions between cancer-specific proteins called oncoproteins , occur largely in tumour cells and thus provide ideal targets for intervention. The proposed project is to develop a model system for a target specific therapy of leukaemia cells by blocking the interactions between oncoproteins. Moreover, the ability to isolate specific blockers of particular protein-protein interactions provides an opportunity to unravel complex genetic pathways in mammalian systems, which are relatively intractable by other analyses. The dissection of pathways using specific blockers may also provide a useful avenue for identifying new drug targets. We have chosen to target particular interactions involving one known oncoprotein in the search for specific inhibitors. A genetic selection will be used to identify random, constrained peptide sequences which are capable of blocking these interactions and which do not interfere with other interactions involving the oncoprotein. This technique allows one to select for or against specific blockers of known interactions from a library containing millions of candidate drug leads in baker's yeast cells. This procedure will be most suitable for high through-put drug screening projects. The validity of this approach to the identification of new peptide drug leads will be finally established in vivo using transgenic models of oncoprotein-dependent cancer in mice.