8r18

Publication Abstract from PubMed

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.

What doesn't fit is made to fit: Pim-1 kinase adapts to the configuration of stilbene-based inhibitors.,Hochban PMM, Heyder L, Heine A, Diederich WE Arch Pharm (Weinheim). 2024 Jun;357(6):e2400094. doi: 10.1002/ardp.202400094. , Epub 2024 Apr 17. PMID:38631036^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.