Rapid Access to Unexplored Chemical Space by Ligand Scanning around a Ruthenium Center: Discovery of Potent and Selective Protein Kinase Inhibitors

An important objective for the discovery of compounds with unique biological activities is the
development of methods for the synthesis of molecular scaffolds with defined three-dimensional shapes.
We are currently investigating the scope of using metal complexes to accomplish this goal. In these
compounds, the metal center has the role of organizing the orientation of the organic ligands, thus defining
the overall shape of the molecule. A strategy is presented that allows a rapid scanning of ligands around
a ruthenium center in the search for ligand spheres that are complementary in shape and functional group
presentation to ATP binding sites of protein kinases. Following this approach, we have identified octahedral
ruthenium complexes as potent inhibitors for the protein kinases Pim1, MSK1, and GSK3α.

发现具备独特生物活性的化合物，其重要目标之一是开发可合成具有确定三维结构的分子骨架（molecular scaffolds）的方法。目前我们正探究利用金属配合物（metal complexes）达成该目标的适用范畴。在这类化合物中，金属中心承担着调控有机配体（organic ligands）取向的功能，进而确定分子的整体空间构象。本文提出一种策略，可实现围绕钌中心（ruthenium center）对配体的快速筛选，以寻找在空间构象与官能团排布上与蛋白激酶（protein kinases）的腺苷三磷酸（ATP）结合位点互补的配体球（ligand spheres）。通过该策略，我们已筛选出八面体钌配合物（octahedral ruthenium complexes），其可作为蛋白激酶Pim1、MSK1及GSK3α的强效抑制剂。