Inhibition of Estrogen Receptor-Dependent Gene Transcription By a Designed Ligant.
Annual rept. 1 Jul 97-30 Jun 98
SCRIPPS CLINIC AND RESEARCH FOUNDATION LA JOLLA CA
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Antiestrogens, like tamoxifen, are currently being used for the treatment of many breast cancers, however, not without significant side effects. We proposed to use small molecules to inhibit binding of estrogen receptor to its DNA target sites, thereby blocking estrogen-responsive gene expression. We have shown that the small hairpin pyrroleimidazole polyamides can be effective inhibitors of gene transcription in living cells. As the first objective, pyrrole-imidazole polyamides will be synthesized to bind sequences adjacent to the estrogen response element and their binding affinity will be determined by quantitative DNase I footprint experiments. For objective two we will determine whether these polyamides inhibit binding of the estrogen receptor to its recognition sequence. In objective three it will be determined whether the polyamides inhibit gene expression in vivo. The laboratory of Peter Dervan has synthesized a polyamide that specifically recognizes the estrogen response element of the pS2 gene. We have shown by quantitave DNase I footprinting experiments that this polyamide binds its recognition site with high affinity and high specificity. We are currently investigating whether this polyamide inhibits binding of recombinant estrogen receptor in vitro. Future studies will focus on the inhibition of transcription of the pS2 gene in living cells by this polyamide.
- Medicine and Medical Research