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 hormone-refractory breast cancer. We have synthesized a pyrimidine-core library of moderate size, members of which act as alpha-helix mimics to block the ERalpha/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 ERalpha/steroid receptor coactivator interaction with K i's in the low mic

SUBMITTER: Parent AA 

PROVIDER: S-EPMC2680390 | biostudies-literature | 2008 Oct

REPOSITORIES: biostudies-literature