Discovery of novel quinoline-based estrogen receptor ligands using peptide interaction profiling.
Traditional approaches to discovery of selective estrogen receptor modulators (SERMs) have relied on ER binding and cell-based estrogen response element-driven assays to identify compounds that are osteoprotective but nonproliferative in breast and uterine tissues. To discover new classes of potential SERMs, we have employed a cell-free microsphere-based binding assay to rapidly characterize ERalpha interactions with conformation-sensing cofactor or phage display peptides. Peptide profiles of constrained triarenes were compared to known proliferative and nonproliferative ER ligands to discover potent quinoline-based ligands with minimal Ishikawa cell stimulation.
Hoekstra
William J
WJ
GlaxoSmithKline Research & Development, Research Triangle Park, North Carolina 27709-3398, USA. william.j.hoekstra@gsk.com
Patel
Hari S
HS
Liang
Xi
X
Blanc
Jean-Baptiste E
JB
Heyer
Dennis O
DO
Willson
Timothy M
TM
Iannone
Marie A
MA
Kadwell
Sue H
SH
Miller
Lisa A
LA
Pearce
Kenneth H
KH
Simmons
Catherine A
CA
Shearin
Jean
J
D000469:Alkaline Phosphatase / Q000096:biosynthesis; D001667:Binding, Competitive; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D002474:Cell-Free System; D004717:Endometrium / Q000166:cytology; D004790:Enzyme Induction; D047628:Estrogen Receptor alpha / Q000187:drug effects / Q000378:metabolism; D047629:Estrogen Receptor beta / Q000187:drug effects / Q000378:metabolism; D005260:Female; D006801:Humans; D008024:Ligands; D008863:Microspheres; D019151:Peptide Library; D011804:Quinolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011960:Receptors, Estrogen / Q000187:drug effects* / Q000378:metabolism; D020845:Selective Estrogen Receptor Modulators / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D008024:Ligands; D019151:Peptide Library; D011804:Quinolines; D011960:Receptors, Estrogen; D020845:Selective Estrogen Receptor Modulators; D000469:Alkaline Phosphatase