Details

Autor(en) / Beteiligte

• Hochban, Phil M M
• Heyder, Lukas
• Heine, Andreas
• Diederich, Wibke E

Titel

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

Ist Teil von

• Archiv der Pharmazie (Weinheim), 2024-04, p.e2400094-e2400094

Ort / Verlag

Germany

Erscheinungsjahr

2024

Link zum Volltext

Quelle

Wiley Online Library Journals Frontfile Complete

Beschreibungen/Notizen

• 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.