Oncology Research, Nerviano Medical Sciences, Viale Pasteur 10, 20014, Nerviano, Italy.
Mol Divers. 2012 Feb;16(1):27-51. doi: 10.1007/s11030-012-9361-6. Epub 2012 Feb 15.
The generation of novel chemotypes in support of our oncology research projects expanded in recent years from a canonical design of kinase-targeted compound libraries to a broader interpretation of purinome-targeted libraries (PTL) addressing the specificity of cancer relevant targets such as kinases and ATPases. Successful screening of structurally diverse ATP-binding targets requires compound libraries covering multiple design elements, which may include phosphate surrogate moieties in ATPase inhibitors or far reaching lipophilic residues stabilizing inactive kinase conformations. Here, we exemplify the design and preparation of drug-like combinatorial libraries and report significantly enhanced screening performance on purinomic targets. We compared overall hit rates of PTL with a simultaneously tested unbiased collection of 200,000 compounds and found consistent superiority of the targeted libraries in all cases. We also analyzed the performance of the largest targeted libraries in comparison with each other and often found striking differences in how a specific target responds to various chemotypes and to whole collections.
近年来，为了支持我们的肿瘤学研究项目，新型化学型的产生已经从经典的激酶靶向化合物库设计扩展到更广泛的嘌呤组靶向库（PTL）设计，以针对癌症相关靶点（如激酶和 ATP 酶）的特异性。成功筛选结构多样的 ATP 结合靶标需要涵盖多种设计元素的化合物库，这些元素可能包括 ATP 酶抑制剂中的磷酸替代基团或稳定无活性激酶构象的深远亲脂性残基。在这里，我们举例说明了药物样组合文库的设计和制备，并报告了嘌呤组靶标筛选性能的显著提高。我们将 PTL 的总命中率与同时测试的 200,000 种化合物的无偏收集进行了比较，在所有情况下都发现靶向文库具有一致的优势。我们还分析了最大靶向文库彼此之间的性能，并且经常发现特定靶标对各种化学型和整个文库的反应存在显著差异。
