Combinatorial Libraries and Cellular Signaling

组合文库的溶液相合成技术的发展与应用 用于筛选旨在确定癌症治疗新药物的新检测方法 都是很详细的。在过去的努力中，已经准备并存档了40,000多个化合物 在现有的图书馆中，这将增加到目前的1,000,000个化合物 格兰特。该库中包含模板和仿真体，作为其扩展的一部分 靶向蛋白质-蛋白质或蛋白质-DNA相互作用。对现有图书馆的筛选 随后的先导优化提供了(1)第一种血管生成抑制剂 基于抑制整合素αvbeta3与MMP2结合而显示体内抗肿瘤活性，(2)抑制c-Myc诱导的细胞的Myc-Max二聚化的第一个小分子抑制剂 转化，(3)细胞内帕西林/α4结合的第一个抑制剂，用于抑制 细胞迁移，(4)相对较小的促红细胞生成素受体激动剂 二聚化；(5)Lef-1/β-catenin介导基因的两类抑制剂 抄写。对这些目标的持续努力将补充关于更多 目标。

The development and application of the solution-phase synthesis of combinatorial libraries for screening in novel assays designed to identify new agents for the treatment of cancer are detailed. In the past efforts, over 40,000 compounds have been prepared and archived in existing libraries and this will be increased to 1,000,000 compounds under the present grant. Included in this library and as part of its expansion are templates and mimetics that target protein-protein or protein-DNA interactions. The screening of the current libraries and the subsequent lead optimization have provided (1) the first angiogenesis inhibitors exhibiting in vivo antitumor activity based on inhibition of MMP2 binding to integrin alphavbeta3, (2) the first small molecule inhibitors of Myc-Max dimerization that inhibit c-Myc-induced cell transformation, (3) the first inhibitors of intracellular Paxillin/alpha4 binding which serve to inhibit cell migration, (4) relatively small EPO agonists that act by promoting EPO receptor dimerization, and (5) two classes of inhibitors of LEF-1/beta-catenin mediated gene transcription. Continued efforts on these targets will complement new studies on additional targets.