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

Afhüppe, Wiebke; Beekman, Johanna M.; Otto, Christiane; Korr, Daniel; Hoffmann, Jens; Fuhrmann, Ulrike; Möller, Carsten

doi:10.1016/j.jsbmb.2009.12.011

Cited by 23 publications

(15 citation statements)

References 48 publications

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“…We characterized the nature of the PF-02413873 interaction with PR in more detail by Schild analysis and assessment on nuclear translocation and LxxLL peptide binding compared with RU-486. RU-486 behaved in these assays as anticipated from previous literature reports, facilitating PR translocation and antagonizing PR function though recruitment of corepressors (Bocquel et al, 1993;Madauss et al, 2007;Afhü ppe et al, 2010). In contrast, PF-02413873 blocked PR nuclear translocation at concentrations that blocked PR function in the T47D functional assay.…”

Section: Discussionsupporting

confidence: 80%

The Translational Efficacy of a Nonsteroidal Progesterone Receptor Antagonist, 4-[3-Cyclopropyl-1-(mesylmethyl)-5-methyl-1H-pyrazol-4-yl]oxy,-2,6-dimethylbenzonitrile (PF-02413873), on Endometrial Growth in Macaque and Human

Howe

Mount²,

Bess³

et al. 2011

J Pharmacol Exp Ther

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There is considerable ongoing investment in the research and development of selective progesterone receptor (PR) modulators for the treatment of gynecological conditions such as endometriosis. Here, we provide the first report on the clinical evaluation of a nonsteroidal progesterone receptor antagonist 4-[3-cyclopropyl-1-(mesylmethyl)-5-methyl-1H-pyrazol-4-yl]oxy,-2,6-dimethylbenzonitrile (PF-02413873) in healthy female subjects. In in vitro assays, PF-02413873 behaved as a selective and fully competitive PR antagonist, blocking progesterone binding and PR nuclear translocation. The pharmacological mode of action of PF-02413873 seems to differ from the founding member of the class of steroidal PR antagonists, 11␤-4-dimethylaminophenyl-17␤-hydroxy-17␣-propinyl-4,9-estradiene-3-one (RU-486; mifepristone). Exposure-effect data from studies in the cynomolgus macaque, however, demonstrated that PF-02413873 reduced endometrial functionalis thickness to a comparable degree to RU-486 and this effect was accompanied by a decrease in proliferation rate (as measured by bromodeoxyuridine incorporation) for both RU-486 and high-dose PF-02413873. These data were used to underwrite a clinical assessment of PF-02413873 in a randomized, double-blinded, third-party open, placebo-controlled, dose-escalation study in healthy female volunteers with dosing for 14 days. PF-02413873 blocked the follicular phase increase in endometrial thickness, the midcycle lutenizing hormone surge, and elevation in estradiol in a dose-dependent fashion compared with placebo. This is the first report of translational efficacy data with a nonsteroidal PR antagonist in cynomolgus macaque and human subjects.

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Section: Discussionsupporting

confidence: 80%

The Translational Efficacy of a Nonsteroidal Progesterone Receptor Antagonist, 4-[3-Cyclopropyl-1-(mesylmethyl)-5-methyl-1H-pyrazol-4-yl]oxy,-2,6-dimethylbenzonitrile (PF-02413873), on Endometrial Growth in Macaque and Human

Howe

Mount²,

Bess³

et al. 2011

J Pharmacol Exp Ther

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“…PR interacts with FGFR-2 and STAT5 in cells treated with FGF2 or with MPA pPR and pSTAT5 act as transcription factors (11,21) and FGFR-2 may be immunolocalized in the nuclei of ligandstimulated cells (3,23,24). FGF2 binds preferentially to FGFR-2 and it may also bind to other members of the FGFR family (25).…”

Section: Mpa and Fgf2 Induce Erk Akt And Stat5 Phosphorylationmentioning

confidence: 99%

Interaction between FGFR-2, STAT5, and Progesterone Receptors in Breast Cancer

et al. 2011

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Fibroblast growth factor (FGF) receptor 2 (FGFR-2) polymorphisms have been associated with an increase in estrogen receptor and progesterone receptor (PR)-positive breast cancer risk; however, a clear mechanistic association between FGFR-2 and steroid hormone receptors remains elusive. In previous works, we have shown a cross talk between FGF2 and progestins in mouse mammary carcinomas. To investigate the mechanisms underlying these interactions and to validate our findings in a human setting, we have used T47D human breast cancer cells and human cancer tissue samples. We showed that medroxyprogesterone acetate (MPA) and FGF2 induced cell proliferation and activation of ERK, AKT, and STAT5 in T47D and in murine C4-HI cells. Nuclear interaction between PR, FGFR-2, and STAT5 after MPA and FGF2 treatment was also showed by confocal microscopy and immunoprecipitation. This effect was associated with increased transcription of PRE and/or GAS reporter genes, and of PR/STAT5-regulated genes and proteins. Two antiprogestins and the FGFR inhibitor PD173074, specifically blocked the effects induced by FGF2 or MPA respectively. The presence of PR/FGFR-2/ STAT5 complexes bound to the PRE probe was corroborated by using NoShift transcription and chromatin immunoprecipitation of the MYC promoter. Additionally, we showed that T47D cells stably transfected with constitutively active FGFR-2 gave rise to invasive carcinomas when transplanted into NOD/SCID mice. Nuclear colocalization between PR and FGFR-2/STAT5 was also observed in human breast cancer tissues. This study represents the first demonstration of a nuclear interaction between FGFR-2 and STAT5, as PR coactivators at the DNA progesterone responsive elements, suggesting that FGFRs are valid therapeutic targets for human breast cancer treatment. Cancer Res; 71(10); 3720-31. Ó2011 AACR.

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“…In this case, the PR ligand complex presents only one different conformation as compared to that of 12. 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] .…”

Section: Crystallographic Studies Of Pr Leading To the Design Of New mentioning

confidence: 99%

“…The antiproliferative activity of steroid 10 ( Figure 4) is explained on the ground that this steroid can attach to the ligand binding domain of PR, a helix 12 conformation. Thus, helix 12 forms a selective surface that binds to co-repressors and; as a result of this, an antiproliferative activity is observed 36 .…”

Section: Crystallographic Studies Of Pr Leading To the Design Of New mentioning

confidence: 99%

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

Cabeza

Heuze

Sánchez

et al. 2014

Journal of Enzyme Inhibition and Medicinal Chemistry

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The role of progesterone in women's cancers as well as the knowledge of the progesterone receptor (PR) structure has prompted the design of different therapies. The aim of this review is to describe the basic structure of PR agonists and antagonists as well as the recent treatments for illness associated with the progesterone receptor. The rational design for potent and effective drugs for the treatment of female cancer must consider the structural changes of the androgen and progestogen skeleton which are an indicator of their activity as progestins or antiprogestins. The presence of a hydroxyl group at C-17 in the progesterone skeleton brings about a loss of progestational activity whereas acetylation induces a progestational effect. The incorporation of an ethynyl functional group to the testosterone framework results in a loss of androgenic activity with a concomitant enhancement of the progestational effect. On the other hand, an ester function at C-3 of dehydroepiandrosterone skeleton induces partial antagonism to the PR.

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

Cited by 23 publications

References 48 publications

The Translational Efficacy of a Nonsteroidal Progesterone Receptor Antagonist, 4-[3-Cyclopropyl-1-(mesylmethyl)-5-methyl-1H-pyrazol-4-yl]oxy,-2,6-dimethylbenzonitrile (PF-02413873), on Endometrial Growth in Macaque and Human

The Translational Efficacy of a Nonsteroidal Progesterone Receptor Antagonist, 4-[3-Cyclopropyl-1-(mesylmethyl)-5-methyl-1H-pyrazol-4-yl]oxy,-2,6-dimethylbenzonitrile (PF-02413873), on Endometrial Growth in Macaque and Human

Interaction between FGFR-2, STAT5, and Progesterone Receptors in Breast Cancer

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

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