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Characterization of Vitamin D Receptor Ligands with Cell-Specific and Dissociated Activity

Instituto de Investigaciones Biomédicas (A.I.C., R.S.-M., A.M.J.-L., A.A.), Consejo Superior de Investigaciones and Universidad Autónoma de Madrid, 28029 Madrid, Spain; and Schering AG (A.S., U.Z.), 13353 Berlin, Germany

Address all correspondence and requests for reprints to: Ana Aranda, Instituto de Investigaciones Biomédicas, Consejo Superior de Investigaciones Científicas and Universidad Autónoma de Madrid, Arturo Duperier 4, 28029 Madrid, Spain. E-mail: aaranda{at}iib.uam.es.

Although the main role of 1,25-dihydroxyvitamin D₃ [1,25-(OH)₂D₃] is to regulate calcium homeostasis, the valuable therapeutic applications of this compound have led to the search of new 1,25-(OH)₂D₃-vitamin D receptor (VDR) ligands with less side effects. In this work we have characterized seven 1,25-(OH)₂D₃ derivatives (ZK136607, ZK161422, ZK157202, ZK159222, ZK168492, ZK191732, and ZK168289). ZK157202 is an agonist that gives a pattern similar to that of 1,25-(OH)₂D₃ or ZK161422 in limited trypsin digestion assays, is able to recruit p160 and VDR-interacting protein 205 coactivators, is as potent as 1,25-(OH)₂D₃ to stimulate vitamin D response element-dependent transcription in HeLa cells, and acts as a superagonist in human embryonic kidney 293T cells. This compound is also more potent than the natural ligand to transrepress the activation of the retinoic acid receptor ß2 promoter by retinoic acid and the response of the collagenase promoter to 4-12-O-tetradecanoylphorbol 13-acetate. ZK136607, ZK168492, ZK191732, and ZK168289 have a profile similar to that of the partial antagonist ZK159222. They induce an antagonistic-type proteolytic pattern, do not recruit classical coactivators, and have little transactivation potency. However, they act in a cell context-dependent manner because they lack activity in HeLa cells while presenting some agonistic activity in human embryonic kidney 293T cells, or vice versa. Furthermore, some of these compounds have a dissociated activity: they cannot transactivate but they are as potent as 1,25-(OH)₂D₃ in transrepression assays. Together our results demonstrate the existence of novel VDR ligands with variable biological functions and dissociated activity. They should represent useful tools for studying VDR function and could have therapeutic utility.

NURSA Molecule Pages Link:

Nuclear Receptors:   RARα  |  RARβ  |  VDR  |  RXRα

Ligands:   Calcitriol

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