Tetra-substituted imidazoles as a new class of inhibitors of the p53-MDM2 interaction
Tetra-substituted imidazoles as a new class of inhibitors of the p53-MDM2 interaction
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DOI：
10.1016/j.bmcl.2014.03.039
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发表时间：
2014-05-01
影响因子：
2.7
通讯作者：
Furet, Pascal
中科院分区：
文献类型：
--
作者：
Vaupel, Andrea;Bold, Guido;Furet, Pascal
利用先前在寻找p53-MDM 2相互作用的非肽抑制剂中获得的晶体结构信息，我们发现了另一类能够破坏这种蛋白质-蛋白质相互作用的新化合物，这是肿瘤药物研究中的重要靶点。新的抑制剂，基于四取代的咪唑支架，已被优化，以低纳摩尔的效力，在生化测定后的结构指导的方法。适当的策略使我们能够在p53依赖性MDM 2扩增细胞系上将高生化效力转化为显著的抗增殖活性。(C)2014爱思唯尔有限公司版权所有。
Capitalizing on crystal structure information obtained from a previous effort in the search for non peptide inhibitors of the p53-MDM2 interaction, we have discovered another new class of compounds able to disrupt this protein-protein interaction, an important target in oncology drug research. The new inhibitors, based on a tetra-substituted imidazole scaffold, have been optimized to low nanomolar potency in a biochemical assay following a structure-guided approach. An appropriate strategy has allowed us to translate the high biochemical potency in significant anti-proliferative activity on a p53-dependent MDM2 amplified cell line. (C) 2014 Elsevier Ltd. All rights reserved.