What doesn't fit is made to fit: Pim‐1 kinase adapts to the configuration of stilbene‐based inhibitors

Abstract

Recently, we have developed novel Pim‐1 kinase inhibitors starting from a dihydrobenzofuran core structure using a computational approach. Here, we report the design and synthesis of stilbene‐based Pim‐1 kinase inhibitors obtained by formal elimination of the dihydrofuran ring. These inhibitors of the first design cycle, which were obtained as inseparable cis/trans mixtures, showed affinities in the low single‐digit micromolar range. To be able to further optimize these compounds in a structure‐based fashion, we determined the X‐ray structures of the protein‐ligand‐complexes. Surprisingly, only the cis‐isomer binds upon crystallization of the cis/trans‐mixture of the ligands with Pim‐1 kinase and the substrate PIMTIDE, the binding mode being largely consistent with that predicted by docking. After crystallization of the exclusively trans‐configured derivatives, a markedly different binding mode for the inhibitor and a concomitant rearrangement of the glycine‐rich loop is observed, resulting in the ligand being deeply buried in the binding pocket.