Efficient discovery of selective small molecule agonists of estrogen-related receptor gamma using combinatorial approach.
With the goal of discovering a selective agonist of estrogen-related receptor gamma (ERRgamma) with enhanced potency, we designed a series of small-molecule ligands derived from a known ERRgamma agonist, GSK4716, that can substantially potentiate the transcriptional activity of ERRgamma. Individual compounds among a 30-member library of acyl hydrazones were pre-evaluated through in silico docking studies on the receptor cavities of ERRgamma LBDs using X-ray crystal structures cocrystallized with GSK4716 and 4-OHT. This rational approach to achieve the enhanced potency in ERRgamma transcriptional activity with selectivity over ERRalpha/beta enables us to complete the construction of a focused library by carrying out microwave-assisted parallel synthesis with excellent yields and purities. Finally, we identified a more potent ERRgamma agonist, E6, with excellent selectivity over ERRalpha/beta.
Kim
Yongju
Y
Department of Chemistry, College of Natural Science, Seoul National University, Seoul 151-747, Korea.
Koh
Minseob
M
Kim
Don-Kyu
DK
Choi
Hueng-Sik
HS
Park
Seung Bum
SB
D020650:Combinatorial Chemistry Techniques; D018360:Crystallography, X-Ray; D055808:Drug Discovery; D006834:Hydrazines / Q000737:chemistry / Q000494:pharmacology; D008958:Models, Molecular; D015394:Molecular Structure; D011960:Receptors, Estrogen / Q000819:agonists*; D013629:Tamoxifen / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology
C490917:ESRRG protein, human; C545235:GSK 4716; D006834:Hydrazines; D011960:Receptors, Estrogen; D013629:Tamoxifen; C016601:afimoxifene