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J. Biol. Chem., Vol. 275, Issue 22, 16506-16512, June 2, 2000

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Antagonistic Action of a 25-Carboxylic Ester Analogue of 1,25-Dihydroxyvitamin D₃ Is Mediated by a Lack of Ligand-induced Vitamin D Receptor Interaction with Coactivators^*

Michaela Herdick, Andreas Steinmeyer^§, and Carsten Carlberg^¶

From the  Institut für Physiologische Chemie I and Biomedizinisches Forschungszentrum, Heinrich-Heine-Universität, D-40001 Düsseldorf, Germany and the ^§ Institut für Arzneimittelchemie, Schering AG, D-13342 Berlin, Germany

A 25-carboxylic ester analogue of 1,25-dihydroxyvitamin D₃ (1,25-(OH)₂D₃), ZK159222, was described as a novel type of antagonist of 1,25-(OH)₂D₃ signaling. The ligand sensitivity of ZK159222, in facilitating complex formation between 1,25-(OH)₂D₃ receptor (VDR) and the retinoid X receptor (RXR) on a 1,25-(OH)₂D₃ response element (VDRE), was approximately 7-fold lower when compared with 1,25-(OH)₂D₃. However, ZK159222 was not able to promote a ligand-dependent interaction of the VDR with the coactivator proteins SRC-1, TIF2, and RAC3, neither in solution nor in a complex with RXR on DNA. Functional analysis in HeLa and COS-7 cells demonstrated a 10-100-fold lower ligand sensitivity for ZK159222 than for 1,25-(OH)₂D₃ and, most interestingly, a potency that was drastically reduced compared with 1,25-(OH)₂D₃. A cotreatment of 1,25-(OH)₂D₃ with a 100-fold higher concentration of ZK159222 resulted in a prominent antagonistic effect both in functional in vivo and in in vitro assays. These data suggest that the antagonistic action of ZK159222 is due to a lack of ligand-induced interaction of the VDR with coactivators with a parallel ligand sensitivity, which is sufficient for competition with the natural hormone for VDR binding.

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