Structure-affinity and structure-residence time relationships of macrocyclic Gαq protein inhibitors.

The macrocyclic depsipeptides YM-254890 (YM) and FR900359 (FR) are potent inhibitors of Gαq/11 proteins. They are important pharmacological tools and have potential as therapeutic drugs. The hydrogenated, tritium-labeled YM and FR derivatives display largely different residence times despite similar structures. In the present study we established a competition-association binding assay to determine the dissociation kinetics of unlabeled Gq protein inhibitors. Structure-affinity and structure-residence time relationships were analyzed. Small structural modifications had a large impact on residence time. YM and FR exhibited 4- to 10-fold higher residence times than their hydrogenated derivatives. While FR showed pseudo-irreversible binding, YM displayed much faster dissociation from its target. The isopropyl anchor present in FR and some derivatives was essential for slow dissociation. These data provide a basis for future drug design toward modulating residence times of macrocyclic Gq protein inhibitors, which has been recognized as a crucial determinant for therapeutic outcome. © 2023 The Authors.

Citation

Jan H Voss, Max Crüsemann, Christian R O Bartling, Stefan Kehraus, Asuka Inoue, Gabriele M König, Kristian Strømgaard, Christa E Müller. Structure-affinity and structure-residence time relationships of macrocyclic Gαq protein inhibitors. iScience. 2023 Apr 21;26(4):106492

PMID: 37091255

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