Onapristone, a progesterone receptor antagonist, as first-line therapy in primary breast cancer

Recent advances in structure of progestins and their binding to progesterone receptors

“…The facility of the complex of antagonist-PR to bind to coactivators or co-repressors is associated with target gene expression. An example of this process is the over expression of corepressors that suppress the partial agonistic effect of 12; whereas the over expression of co-activators improves the partial agonistic activity of this steroid [31][32][33][34] . Nevertheless, the binding of 13 to the PR ( Figure 4) shows different properties, since the antagonistic activity of this steroid is not affected by the expression of coactivators or co-repressors molecules.…”

“…This fact could explain why 10 was more effective than 12 or 13 by considering the presence of co-activators 35,36 . On the bases of their effect as pure antagonist, different types of PR antagonists were identified and described; this prevents the binding of PR complex to DNA (13, Figure 4) [32][33][34] . Partial antagonists are those which facilitate the binding of the ligandjoin PR to the progesterone response element (PRE) present in DNA helix; however, they show also an agonistic activity in the target tissues (12, 11, Figure 3) 35 .…”

Progesterone Resistance and Targeting the Progesterone Receptors: A Therapeutic Approach to Endometriosis

“…The development of selective and safe steroidal PRAs has been challenging, both due to reported hepatoxicity as well as potential dose-limiting anti-glucocorticoid effects, due to lack of selectivity (Robertson et al, 1999). More recently, an additional concern has emerged following histological evaluations of subjects dosed for more than 3 months on steroidal PRAs.…”

“…Given the anti-proliferative effects observed in vitro and in vivo for PRAs (Freeburg et al, 2009b;Goyeneche et al, 2007;Ohara et al, 2007;Poole et al, 2006;Tieszen et al, 2011), the broader utility of this class in treating other benign and malignant growth conditions has not gone unnoticed Robertson et al, 1999;Rocereto et al, 2000;Wilkens et al, 2008). In the closely related condition of uterine fibroids, small studies have demonstrated a reduction in myoma volume and uterine bleeding with asoprisnil and RU-486 (Chabbert-Buffet et al, 2005;DeManno et al, 2003;Fiscella et al, 2006).…”

Progesterone receptor modulators in breast cancer

“…Nevertheless, both compounds went into clinical trials. In the case of ZK 299, phase II trials were terminated early due to liver toxicity found by liver function tests (Robertson et al, 1999). We at Repros Therapeutics have also found liver toxicity at high doses as well but believe that an optimal dosing regimen in terms of oral dose concentration as well as an appropriate schedule is required.…”