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

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Department of Chemistry, University of Illinois at Urbana−Champaign, 600 South Mathews Avenue, Urbana, Illinois 61801
* To whom correspondence should be addressed. Phone: 217-333-6310. Fax: 217-333-7325. E-mail: [email protected]
Cite this: J. Med. Chem. 2008, 51, 20, 6512–6530
Publication Date (Web):September 12, 2008
Copyright © 2008 American Chemical Society

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    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 α-helix mimics to block the 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 Ki′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.

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