The combination of doxorubicin and paclitaxel is highly active, but is accompanied by the dose-limiting toxic effects of neutropenia, neuropathy and cardiotoxicity.
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 G 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 G inhibitory activity. This provides pertinent information for the understanding of the G inhibitory mechanism by this class of compounds and importantly provides a pathway for the development of labeled YM-254890 analogues.
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/11inhibitor among the new analogues. This study provides information for the future design of potent and simplified YM‐254890 analogues.
Heterotrimeric G proteins are essential mediators of intracellular signaling of G protein-coupled receptors. The Gq/11subfamily consists of Gq, G11, G14 and G16 proteins of which all but G16 are inhibited by the structurally related natural products YM-254890 and FR900359. These inhibitors act by preventing the GDP/GTP exchange, which is necessary for activation of all G proteins. A homologous putative binding site for YM-254890/FR900359 can also be found in members of the other three G protein families; Gs, Gi/o and G12/13, but none of the published analogs of YM-254890/FR900359 have shown any inhibitory activity for any of these. To explain why the YM-254890/FR900359 scaffold only inhibits Gq/11/14, the present study delineated the molecular selectivity determinants by exchanging amino acid residues in the YM-254890/FR900359 binding site in Gq and Gs. We found that the activity of a Gs mutant with a Gq-like binding site for YM-254890/FR900359 can be inhibited by FR900359 and a minimum of three mutations are necessary to introduce inhibition in Gs. In all, this suggest that although the YM-254890/FR900359 scaffold has proven unsuccessful to derive Gs, Gi/o and G12/13 inhibitors, the mechanism of inhibition between families of G proteins is conserved opening up for targeting by other, novel inhibitor scaffolds. In lack of a selective Gαs inhibitor, FR900359 sensitive Gas mutants may prove useful in studies where delicate control over Gαs signaling would be of the essence.
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