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Endocrinology Vol. 143, No. 3 941-947
Copyright © 2002 by The Endocrine Society

RECEPTORS

Antagonists Selective for Estrogen Receptor {alpha}

Jun Sun, Ying R. Huang, William R. Harrington, Shubin Sheng, John A. Katzenellenbogen and Benita S. Katzenellenbogen

Departments of Molecular and Integrative Physiology (J.S., W.R.H., S.S., B.S.K.) and Chemistry (Y.R.H., J.A.K.), University of Illinois and University of Illinois College of Medicine, Urbana, Illinois 61801

Address all correspondence and requests for reprints to: Dr. Benita S. Katzenellenbogen, Department of Molecular and Integrative Physiology, 407 South Goodwin Avenue, 524 Burrill Hall, University of Illinois, Urbana, Illinois 61801-3704. E-mail: . katzenel{at}life.uiuc.edu

To develop compounds that are antagonists on ER{alpha}, but not ERß, we have added basic side-chains typically found in nonsteroidal antiestrogens to pyrazole compounds that bind with much higher affinity to ER{alpha} than to ERß. In this way we have developed basic side-chain pyrazoles (BSC-pyrazoles) that are high affinity, potent, selective antagonists on ER{alpha}. These BSC-pyrazoles are themselves inactive on ER{alpha} and ERß, and they antagonize E2 stimulation by ER{alpha} only. We investigated seven basic side-chain substituents on various alkyl-triaryl-substituted pyrazoles, and the most ER{alpha}-selective compound was methyl-piperidino-pyrazole (MPP). ER{alpha}-selective antagonism was observed on diverse reporter-promoter gene constructs containing estrogen response elements that are consensus, nonconsensus (pS2), or comprised of multiple half-estrogen response elements (NHERF/EBP50) and on genes in which ER works indirectly by tethering to other DNA-bound proteins (TGFß3). In contrast to these BSC-pyrazoles, the antiestrogens trans-hydroxytamoxifen, raloxifene, and ICI 182,780 suppress E2 activity via both ER{alpha} and ERß. The most effective BSC-pyrazole, MPP, fully antagonized E2 stimulation of pS2 mRNA in MCF-7 breast cancer cells, consistent with the fact that these cells contain almost exclusively ER{alpha}. These compounds should be useful in studying the biological functions of ER{alpha} and ERß and in selectively blocking responses that are mediated through ER{alpha}.




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