Structure-guided synthesis of tamoxifen analogs with improved selectivity for the orphan ERRgamma.
The design and synthesis of 4-hydroxytamoxifen (4-OHT) derivatives are described. The binding affinities of these compounds toward the orphan estrogen-related receptor gamma and the classical estrogen receptor alpha demonstrate that analogs bearing hydroxyalkyl groups display improved binding selectivity profiles compared with that of 4-OHT. An X-ray crystal structure of one of the designed compounds bound to ERRgamma LBD confirms the molecular basis of the selectivity.
Chao
Esther Y H
EY
Discovery Research, GlaxoSmithKline, Five Moore Drive, Research Triangle Park, NC 27709, USA.
Collins
Jon L
JL
Gaillard
Stéphanie
S
Miller
Aaron B
AB
Wang
Liping
L
Orband-Miller
Lisa A
LA
Nolte
Robert T
RT
McDonnell
Donald P
DP
Willson
Timothy M
TM
Zuercher
William J
WJ
D001665:Binding Sites / Q000187:drug effects; D018360:Crystallography, X-Ray; D015195:Drug Design; D047628:Estrogen Receptor alpha / Q000187:drug effects; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D015394:Molecular Structure; D018160:Receptors, Cytoplasmic and Nuclear / Q000187:drug effects*; D011960:Receptors, Estrogen / Q000187:drug effects*; D013329:Structure-Activity Relationship; D013629:Tamoxifen / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000494:pharmacology
C490917:ESRRG protein, human; D047628:Estrogen Receptor alpha; D008024:Ligands; D018160:Receptors, Cytoplasmic and Nuclear; D011960:Receptors, Estrogen; D013629:Tamoxifen