Discovery of AICAR Tfase inhibitors that disrupt requisite enzyme dimerization
Discovery of AICAR Tfase inhibitors that disrupt requisite enzyme dimerization
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DOI：
10.1016/j.bmcl.2005.03.094
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发表时间：
2005-06-02
影响因子：
2.7
通讯作者：
Boger, DL
中科院分区：
文献类型：
--
作者：
Capps, KJ;Humiston, J;Boger, DL
通过筛选拟肽文库（> 40,000 种化合物），发现了一类新型氨基咪唑甲酰胺核糖核苷酸转化酶 (AICAR Tfase) 抑制剂，该抑制剂通过抑制必需的酶二聚化发挥作用。除了定义负责活性的先导化合物的关键结构特征外，对非常小的抑制剂的动力学分析还确定它们作为 AICAR Tfase 的非竞争性解离抑制剂，其中原型先导化合物（A1B3，Cappsin 1）的 K-i 为 3.1 +/- 0.3 mu M。因此，这些研究定义了一种独特的方法，可以选择性地靶向 AICAR Tfase，而不是所有其他叶酸依赖性酶，并且它仅代表一种通过破坏必要的酶二聚化来实现抑制的一些酶已经从筛选无偏组合文库中出现。 (c) 2005 Elsevier Ltd. 保留所有权利。
The discovery of a new class of aminoimidazole carboxamide ribonucleotide transformylase (AICAR Tfase) inhibitors through screening peptidomimetic libraries (> 40,000 compounds) that act by inhibiting requisite enzyme dimerization is disclosed. In addition to defining key structural features of the lead compounds responsible for the activity, kinetic analysis of the remarkably small inhibitors established that they act as noncompetitive, dissociative inhibitors of AICAR Tfase with the prototypical lead (A1B3, Cappsin 1) exhibiting a K-i of 3.1 +/- 0.3 mu M. Thus, the studies define a unique approach to selectively targeting AICAR Tfase over all other folate-dependent enzymes, and it represents only one of a few enzymes for which inhibition achieved by disrupting requisite enzyme dimerization has emerged from screening unbiased combinatorial libraries. (c) 2005 Elsevier Ltd. All rights reserved.