Bicyclo[2.2.2]octanes: close structural mimics of the nuclear receptor-binding motif of steroid receptor coactivators.
Nuclear hormone receptor (NR) function relies on association of agonist-bound receptors with steroid receptor coactivator (SRC) proteins through a small pentapeptide motif (LXXLL) of the SRC that binds to a hydrophobic groove on the NR. We have synthesized a series of bicyclo[2.2.2]octanes that are close structural mimics of the two key leucine residues of this SRC sequence as bound in the hydrophobic groove of the estrogen receptor. These bicyclic systems block the NR-SRC interaction with modest potency.
Zhou
Hai-Bing
HB
Department of Chemistry, University of Illinois, 600 South Mathews Avenue, Urbana, IL 61801, USA.
Collins
Margaret L
ML
Gunther
Jillian R
JR
Comninos
John S
JS
Katzenellenbogen
John A
JA
D000595:Amino Acid Sequence; D001665:Binding Sites; D001643:Bridged Bicyclo Compounds / Q000737:chemistry* / Q000494:pharmacology; D031541:Fluorescence Resonance Energy Transfer; D051548:Histone Acetyltransferases / Q000737:chemistry / Q000378:metabolism*; D008958:Models, Molecular; D018716:Molecular Mimicry; D008969:Molecular Sequence Data; D015394:Molecular Structure; D056920:Nuclear Receptor Coactivator 1; D014157:Transcription Factors / Q000737:chemistry / Q000378:metabolism*
D001643:Bridged Bicyclo Compounds; D014157:Transcription Factors; D051548:Histone Acetyltransferases; D056920:Nuclear Receptor Coactivator 1