Estrogen receptors (ERs) play a central role in the diverse actions of estrogen. A number of synthetic ER ligands have been generated that can modulate various ER functions. Here we show that TAS-108, representing a novel class of synthetic ER ligands, blocked both ER transactivation functions without inhibiting DNA-binding activity. A transient expression assay showed that similar to IC1182,780, TAS-108 exhibited pure antagonistic activity as it blocked both the N-terminal AF-1 and C-terminal AF-2 transactivation functions. However, unlike IC1182,780, TAS-108 promoted the recruitment of the SMRT co-repressor that abolished ER transactivation function without inhibition of the ability of ERwalpha to bind to its target DNA. Both TAS-108 and IC1182,780 acted as antagonists for the transactivation functions of the D351Y mutant, derived from tamoxifen-resistant breast cancer cells, while estrogen and known selective estrogen receptor modulators (SERMs), 4-OH tamoxifen and raloxifene, stimulated D351Y-mediated transcription. Thus, our findings indicated that TAS-108 acts as a novel estrogen antagonist that recruits co-repressors to ERs without AF-1 activation or prevention of DNA binding. Therefore, TAS-108 may be effective against tamoxifen-resistant breast cancer via a different mechanism than that for ICI182,780. (C) 2003 Elsevier Inc. All rights reserved.