In vitro characterization of ZK 230211--A type III progesterone receptor antagonist with enhanced antiproliferative properties.

The progesterone receptor (PR) is a key regulator of female reproductive functions. Compounds with progesterone inhibiting effects (PR antagonists) have found numerous utilities in female reproductive health, ranging from contraception to potential treatment of progesterone-dependent diseases like uterine leiomyomas. Based on in vitro characteristics such as DNA binding activity and partial agonistic transcriptional behavior in the presence of protein kinase A activators (cyclic-AMP), three types of PR modulators with antagonistic properties have been defined. In this study, we analyzed the in vitro characteristics of the PR antagonist ZK 230211 in comparison to the classical antagonists onapristone and mifepristone. We focused on PR actions in genomic signaling pathways, including DNA binding activity, nuclear localization and association with the nuclear receptor corepressor (NCoR) as well as actions in non-genomic signaling, such as the activation of c-Src kinase signaling and cyclin D1 gene promoter activity. ZK 230211 represents a type of PR antagonist with increased inhibitory properties in comparison to mifepristone and onapristone. When liganded to the progesterone receptor, ZK 230211 induces a strong and persistent binding to its target response element (PRE) and increases NCoR recruitment in CV-1 cells. Furthermore, ZK 230211 displays less agonistic properties with regard to the association of PR isoform B and the cytoplasmic c-Src kinase in HeLa cells. It represses T47D cell cycle progression, in particular estradiol-induced S phase entry. In summary, our studies demonstrate ZK 230211 to be a type III progesterone receptor antagonist which is characterized by very strong DNA binding activity and strong antiproliferative effects in the cancer cell lines HeLa and T47D. Copyright 2010 Elsevier Ltd. All rights reserved.