Structure-Activity Relationship Studies of the Cyclic Depsipeptide Natural Product YM-254890, Targeting the Gq Protein

ChemMedChem
Hang ZhangKristian Strømgaard

Abstract

Extracellular signals perceived by G protein-coupled receptors are transmitted via G proteins, and subsequent intracellular signaling cascades result in a plethora of physiological responses. The natural product cyclic depsipeptides YM-254890 and FR900359 are the only known compounds that specifically inhibit signaling mediated by the Gq subfamily. In this study we exploit a newly developed synthetic strategy for this compound class in the design, synthesis, and pharmacological evaluation of eight new analogues of YM-254890. These structure-activity relationship studies led to the discovery of three new analogues, YM-13, YM-14, and YM-18, which displayed potent and selective Gq inhibitory activity. This provides pertinent information for the understanding of the Gq inhibitory mechanism by this class of compounds and importantly provides a pathway for the development of labeled YM-254890 analogues.

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Sep 29, 2018·Nature Reviews. Drug Discovery·Adrian P Campbell, Alan V Smrcka
Feb 13, 2019·The Journal of Biological Chemistry·Davide MalfaciniEvi Kostenis
Aug 6, 2020·The Journal of Biological Chemistry·Michael W BoesgaardHans Bräuner-Osborne
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