Structure-Activity Relationship Studies of the Natural Product Gq/11 Protein Inhibitor YM-254890

ChemMedChem
Xiao-Feng XiongKristian Strømgaard

Abstract

G proteins act as molecular switches in G protein-coupled receptor signaling pathways and are key mediators for numerous important physiological processes. The natural product, cyclic depsipeptide YM-254890, together with the structurally similar FR900359, is the only known selective inhibitor of the Gq/11 subfamily of G proteins. We recently reported the first total synthesis of YM-254890 and FR900359, followed by synthesizing analogues to perform structure-activity relationship studies. However, incomplete information about their structure-activity relationship prevents the further development of potent and structurally simplified analogues. Herein we report the first systematic structure-activity relationship study toward the N-methyldehydroalanine moiety in YM-254890, by designing and synthesizing seven new analogues. Pharmacological characterization of the seven compounds for Gq/11 -, Gi/o - and Gs -mediated signaling showed that the simplified analogue YM-19 is the most potent Gq/11 inhibitor among the new analogues. This study provides information for the future design of potent and simplified YM-254890 analogues.

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Citations

Jan 24, 2019·Pest Management Science·Beth A LorsbachKevin G Meyer
Jun 21, 2019·Cancers·Michela CroceRosaria Gangemi
Aug 6, 2020·The Journal of Biological Chemistry·Michael W BoesgaardHans Bräuner-Osborne
Oct 1, 2020·Cancers·Fabiana MalloneAntonietta Moramarco
Jun 21, 2019·Medicinal Research Reviews·Hang ZhangKristian Strømgaard
Jan 10, 2021·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Wolfgang Sippl, Fidele Ntie-Kang
Apr 17, 2021·ACS Pharmacology & Translational Science·Jonathan G SchlegelChrista E Müller

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