Optimization of a Dibenzodiazepine Hit to a Potent and Selective Allosteric PAK1 Inhibitor
Optimization of a Dibenzodiazepine Hit to a Potent and Selective Allosteric PAK1 Inhibitor
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DOI：
10.1021/acsmedchemlett.5b00102
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发表时间：
2015-07-01
影响因子：
4.2
通讯作者：
Marzinzik, Andreas L.
中科院分区：
文献类型：
--
作者：
Karpov, Alexei S.;Amiri, Payman;Marzinzik, Andreas L.
针对新的变构蛋白激酶位点的抑制剂的发现是非常具有挑战性的。然而，这种化合物一旦被鉴定出来，就可以在整个基因组中提供极高水平的选择性。在这里，我们报道了我们的基于结构的二苯二氮卓类HIT 1的优化策略，它是在基于片段的筛选中发现的，产生了PAK1的高效和选择性的抑制剂，如2和3。化合物2与PAK1共结晶以确认与变构位点的结合并揭示新的关键相互作用。化合物3在细胞水平上调节PAK1，由于其选择性，使得有价值的研究能够询问PAK1激酶的生物学功能。
The discovery of inhibitors targeting novel allosteric kinase sites is very challenging. Such compounds, however, once identified could offer exquisite levels of selectivity across the kinome. Herein we report our structure-based optimization strategy of a dibenzodiazepine hit 1, discovered in a fragment-based screen, yielding highly potent and selective inhibitors of PAK1 such as 2 and 3. Compound 2 was cocrystallized with PAK1 to confirm binding to an allosteric site and to reveal novel key interactions. Compound 3 modulated PAK1 at the cellular level and due to its selectivity enabled valuable research to interrogate biological functions of the PAK1 kinase.