Blocking Estrogen Signaling After the Hormone: Pyrimidine-Core Inhibitors of Estrogen Receptor-Coactivator Binding

Abstract

As an alternative approach to blocking estrogen action, we have developed small molecules that directly disrupt the key estrogen receptor (ER)/coactivator interaction necessary for gene activation. The more direct, protein-protein nature of this disruption might be effective even in hormonerefractory breast cancer. We have synthesized a pyrimidine-core library of moderate size, members of which act as α-helix mimics to block ERα/coactivator interaction. Structure-activity relationships have been explored with various C, N, O and S-substituents on the pyrimidine core. Time-resolved fluorescence resonance energy transfer and cell-based reporter gene assays show that the most active members inhibit the ERα/steroid receptor coactivator interaction with K i 's in the low micromolar range. Through these studies, we have obtained a refined pharmacophore model for activity in this pyrimidine series. Furthermore, the favorable activities of several of these compounds support the feasibility that this coactivator binding inhibition mechanism for blocking estrogen action might provide a potential alternative approach to endocrine therapy.

Methylsulfonylnitrobenzoates, a New Class of Irreversible Inhibitors of the Interaction of the Thyroid Hormone Receptor and Its Obligate Coactivators That Functionally Antagonizes Thyroid Hormone

“…Several selective nuclear receptor modulators have been developed that directly inhibit the binding interaction between receptors and coactivators without affecting ligand binding. Examples include pyrimidines for ER␣ (60,61), hydroxytamoxifen for ER␤ (62,63), ketoconazoles for PXR (64,65), and ␤-aminoketones for TR (30,32,34). However, these inhibitors exhibit either poor potency in cellular models or intolerable toxicity in vivo.…”

International Union of Basic and Clinical Pharmacology. XC. Multisite Pharmacology: Recommendations for the Nomenclature of Receptor Allosterism and Allosteric Ligands

“…A range of peptides, peptidomimetics, and nonpeptide small molecules that inhibit the activity of a variety of NHRs even when agonists are present has been designed over the past decade (Chang et al, , 2005Norris et al, 1999;Hall et al, 2000;Nguyen et al, 2002;Kern and Zuiderweg, 2003;Leduc et al, 2003;Pike et al, 2003;Geistlinger et al, 2004;Arnold et al, 2005Arnold et al, , 2007Galande et al, 2005;Wang et al, 2006;Estebanez-Perpina et al, 2007a;Mettu et al, 2007;LaFrate et al, 2008;Parent et al, 2008); these are sometimes referred to as coactivator binding inhibitors. Coactivator binding inhibitors target the receptor at a site spatially distinct from the orthosteric site, leading to modulation of receptor activity.…”

Small Molecule Inhibitors as Probes for Estrogen and Androgen Receptor Action

“…The unique ability of AR to bind larger motifs such as FXXLF and WXXVW in phage display libraries (15) suggested an approach to selectively targeting AR. Gunther et al (16) re-evaluated a library of coactivator-binding inhibitors originally tested on ER (17). Their idea was that pyrimidines containing large aromatic substituents would retain the ability to bind AR but not ER␣.…”

“…Katzenellenbogen and co-workers (25) used a fluorescence polarization assay to identify pyrimidines that inhibit binding of a coactivator peptide from SRC1 to ER␣. To optimize these compounds, they synthesized a larger pyrimidine-based library (17) and evaluated the compounds using time-resolved FRET (26). Further studies showed that these compounds inhibited ER␣-mediated activation of a transiently transfected luciferase reporter gene.…”