TY - JOUR
T1 - Structure–Activity Relationship Studies of the Natural Product G
q/11
Protein Inhibitor YM-254890
AU - Xiong, Xiao Feng
AU - Zhang, Hang
AU - Boesgaard, Michael W.
AU - Underwood, Christina R.
AU - Bräuner-Osborne, Hans
AU - Strømgaard, Kristian
PY - 2019/4/17
Y1 - 2019/4/17
N2 -
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 G
q/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 G
q/11
-, G
i/o
- and G
s
-mediated signaling showed that the simplified analogue YM-19 is the most potent G
q/11
inhibitor among the new analogues. This study provides information for the future design of potent and simplified YM-254890 analogues.
AB -
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 G
q/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 G
q/11
-, G
i/o
- and G
s
-mediated signaling showed that the simplified analogue YM-19 is the most potent G
q/11
inhibitor among the new analogues. This study provides information for the future design of potent and simplified YM-254890 analogues.
KW - G protein inhibitors
KW - G protein-coupled receptors
KW - G proteins
KW - structure–activity relationships
KW - YM-254890
U2 - 10.1002/cmdc.201900018
DO - 10.1002/cmdc.201900018
M3 - Journal article
C2 - 30790465
AN - SCOPUS:85063194864
SN - 1860-7179
VL - 14
SP - 865
EP - 870
JO - ChemMedChem
JF - ChemMedChem
IS - 8
ER -