Bicyclo[2.2.2]octanes: Close structural mimics of the nuclear receptor-binding motif of steroid receptor coactivators

Abstract

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 lysine 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.Nuclear receptors (NRs) are transcription factors that control many physiological and pathological processes by directly regulating the expression of select target genes. 1 Members of the NR gene superfamily have multi-domain structures, with a conserved DNAbinding domain and a ligand-binding domain (LBD). The transcriptional activity of NRs is initiated by hormone binding that stabilizes the conformation of the LBD. When an agonist ligand binds, conformational stabilization rigidifies surface features that function as docking sites for coactivator protein complexes that are recruited to modify chromatin structure and activate RNA polymerase II. The most notable of these are the p160 class of steroid receptor coactivators (SRCs). 2,3 X-ray crystallography has revealed details of these NR-SRC interactions, 4-9 which are largely mediated by a short, conserved, pentapeptide LXXLL (L=leucine, X=amino acid) motif of the SRC, termed the NR box. The interaction between the estrogen receptor α (ERα) LBD and a peptide corresponding to NR box 2 of SRC1 (RHKILHRLLQE) is shown in Fig. 1. 5 Selected residues of the peptide interact with the LBD through a two-turn amphipathic α-helical motif that places the first and third leucine residues (L690 and L694) in a deep, solvent-exposed hydrophobic groove made up of residues from various helices of the LBD; histidine and arginine residues of the peptide (H691 and R692, removed for clarity) are solvent exposed and appear unnecessary for the interaction. 5 The intrinsic dipole moment of the coactivator α-helix is aligned with charged residues on the surface of the ERα-LBD (E542 interacts with the peptide N-terminus and K362 with its C-terminus), together forming a "charge clamp". 5The traditional strategy to block agonist signaling of NRs involves hormone antagonists (antihormones) that bind to the LBD, displacing the agonist and stabilizing alternative © 2007 Elsevier Ltd. All rights reserved. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. An alternative approach to interrupting NR signaling is the use of compounds capable of blockin...

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