Selective Progesterone Receptor Modulators-Mechanisms and Therapeutic Utility

Abstract

Selective progesterone receptor modulators (SPRMs) are a new class of compounds developed to target the progesterone receptor (PR) with a mix of agonist and antagonist properties. These compounds have been introduced for the treatment of several gynecological conditions based on the critical role of progesterone in reproduction and reproductive tissues. In patients with uterine fibroids, mifepristone and ulipristal acetate have consistently demonstrated efficacy, and vilaprisan is currently under investigation, while studies of asoprisnil and telapristone were halted for safety concerns. Mifepristone demonstrated utility for the management of endometriosis, while data are limited regarding the efficacy of asoprisnil, ulipristal acetate, telapristone, and vilaprisan for this condition. Currently, none of the SPRMs have shown therapeutic success in treating endometrial cancer. Multiple SPRMs have been assessed for efficacy in treating PR-positive recurrent breast cancer, with in vivo studies suggesting a benefit of mifepristone, and multiple in vitro models suggesting the efficacy of ulipristal acetate and telapristone. Mifepristone, ulipristal acetate, vilaprisan, and asoprisnil effectively treated heavy menstrual bleeding (HBM) in patients with uterine fibroids, but limited data exist regarding the efficacy of SPRMs for HMB outside this context. A notable class effect of SPRMs are benign, PR modulator-associated endometrial changes (PAECs) due to the actions of the compounds on the endometrium. Both mifepristone and ulipristal acetate are effective for emergency contraception, and mifepristone was approved by the US Food and Drug Administration (FDA) in 2012 for the treatment of Cushing's syndrome due to its additional antiglucocorticoid effect. Based on current evidence, SPRMs show considerable promise for treatment of several gynecologic conditions.

Keywords: asoprisnil; breast cancer; mifepristone; ulipristal acetate; uterine fibroid; vilaprisan.

Graphical Abstract

Figure 1.

Progesterone role in reproductive diseases. Progesterone synthesis starts with the signal from the hypothalamus to the pituitary gland to release FSH and LH, which further stimulate ovaries to produce progesterone. Progesterone primarily regulates female reproductive function and breast development. Binding of progesterone at its receptor differentially affects tissue growth at its various sites of action. Progesterone is thought to be stimulatory for uterine fibroid growth, while it is protective for endometrial cancer and endometriosis. The effect of progesterone on breast cancer is complex and variable. Progesterone plays a role in the growth and development of uterine fibroids through stimulation of cell proliferation and facilitating extracellular matrix accumulation. This occurs through activation of the AKT and TGF-β3 pathways and the effects of their downstream intermediaries. Progesterone is thought to negatively impact the development of endometriosis; a reduction in P4-regulated genes and PR-B expression in stromal cells has been reported in endometriotic lesions. Progesterone is thought to play a protective role in the development of some endometrial cancers through downregulation of the TGF-β signaling cascades, with the downstream effect inhibiting the growth of endometrial epithelial cells and reducing cancer cell viability and invasion. In the breast, the role of progesterone is complex and controversial. P4 has been shown to drive proliferation, survival, invasion, and angiogenesis of breast cancer cells through the EGF and Wnt-1 pathway, as well as various other intermediaries. In contrast, progestin has also been shown to induce MKP-1 (MAPK phosphatase 1) expression in a PR-dependent fashion as a means of inducing antiproliferative effects.

Figure 2.

Progesterone receptors and their activation. A: Structural and functional properties of progesterone receptor isoforms. PR-B is a protein of 933 amino acids, while PR-A lacks 164 amino acids of PR-B at N-terminal region. The common structural elements include highly variable NTD, DBD, H region, and LBD. PR-B consists of 2 transcription activation functions, (AF)-1 and AF-3, but PR-A consists of only AF-1 located at NTD. AF-2 located at LBD presents in both PR isoforms. Hinge region is involved in the binding of DNA and coregulators, and the dimerization of receptors following active transport of PR into the nucleus. Other truncated progesterone receptor isoforms are demonstrated below the shaded box. PR-C contains deletions at the amino terminus that likely result from an alternative location for translation initiation. PR-S and PR-T likely give rise to identical proteins that are truncated at the amino-terminus due to retention of an intronic sequence termed exon S or exon T, respectively. They both retain transcription of H and LBD. PR-M contains a novel 16 amino acid amino-terminal sequence encoded by a sequence in the distal third intron of the PR gene, followed by exons 4 through 8 of the original PR gene. PR-i45 retains 2 intronic sequences termed exons i45a and i45b. This leads to a change in the reading frame, which causes a truncated protein that lacks a functional LBD and DBD. B: Schematic diagram of mPR protein showing extracellular (gray), 7-transmembrane (orange), and cytoplasmic (clear) domains predicted by several programs. C: PGRMC1 is comprised of a single N-terminal TM and a Cyt b5 domain. The protein has sites for interaction with SH (Src-homology)-2 and SH-3 domains of Src tyrosine kinases, kinase binding sites, and a phosphorylation site for tyrosine and serine/threonine kinases. D and E: Progesterone receptor-mediated genomic and nongenomic signaling pathways. Genomic signaling begins with progesterone binding to nuclear receptors (PR-A and PR-B), which induces receptor activation and leads to dissociation with heat shock proteins (HSP90, HSP70, and HSP40), following dimerization and translocation into the nucleus where they bind with PREs within the promoter of target genes. It is the subsequent interaction of the transcription complex with specific coregulators and transcription factors that initiate the transcriptional activation or suppression of target genes. Liganded PR can also activate transcription of genes, the promoters of which lack PREs by acting as a bridge between transcription factors and coactivators at promoters containing activator protein 1 (AP-1), specificity protein1 (Sp1), signal transducer and activator of transcription 5 (STAT5), and NF-κB sites. Progesterone elicits nongenomic actions through binding with membrane-bound progesterone receptors (mPRs: mPRα, mPRβ, and mPRγ; and PGRMC1) or cytoplasmic PRs following association with cytoplasmic kinase cascades (such as cSrc) and downstream signaling pathways. These include (MAPK, Ca2+ infiux/PKC activation, and the PI3K/AKT pathway. P4 exerts nongenomic actions through PGRMC1 via association with SERBP1 and downstream signaling through the cAMP and Jak/Stat kinase signaling pathways.

Figure 3.

The chemistry and development of selective progesterone receptor modulators. Mifepristone was developed by the French company Roussel Uclaf S.A. It possesses antiprogesterone and antiglucocorticoid effects. Mifepristone has been approved by the FDA in February 2012 for Cushing’s syndrome. Asoprisnil was developing by Schering AG and TAP Pharmaceutical Products. The clinical trial of asoprisnil was suspended in 2007 due to the association with adverse endometrial changes. The development of ulipristal acetate began as CDB-2914 at the NIH and UPA has been approved in Canada and Europe for uterine fibroid treatment, as well as for EC in the United States. Telapristone acetate was also first developed at the NIH in 2000 and is currently under license at Repros Therapeutics Inc. The clinical development of telapristone acetate was suspended in 2009 due to liver toxicity, but studies have been restarted with lower doses. Vilaprisan is under development by Bayer HealthCare Pharmaceuticals. It is currently under investigation in phase III trials for long-term treatment of uterine fibroids.

Figure 4.

Mechanism of action of SPRMs. SPRMs mediate their effects on target cells by binding with PRs at different degrees that induces the recruitment of specific coactivators and corepressors following the modulation of the transcription of target genes.

Figure 5.

Pharmacokinetics and metabolism of SPRMs. Oral administration of SPRMs is frequently absorbed in the gastrointestinal tract and transported directly to the liver. All the SPRMs are primarily metabolized in the liver by cytochromes. Monodemethylated, didemethylated, and hydroxylated metabolites of mifepristone are produced by demethylation and hydroxylation metabolic pathway. The asoprisnil metabolites are produced by 17β-O-demethylation, which further conjugated with glutathione (SG). Like mifepristone, telapristone acetate and ulipristal acetate UPA produce mono and didemethylated metabolites, as well as hydroxylated metabolite. It has been proposed that vilaprisan undergoes reduction to produce hydroxyl derivatives, which further oxidate to produce various metabolites. All the SPRM metabolites are further catalyzed by CYP3A4 and aldoketoreductases. The unabsorbed parent compounds and metabolites are eliminated via urine and feces.

Figure 6.

Molecular mechanisms of clinical efficacy of SPRMs in uterine fibroid, endometriosis, endometrial cancer, and breast cancer. SPRMs effectively inhibit the development of various disease processes through the involvement of multiple mediators (black) that are implicated in various mechanisms of growth (blue). The growth of uterine fibroids is inhibited by all 4 SPRMs (ulipristal acetate, mifepristone, telapristone, and asoprisnil). The mechanism of this effect is multifactorial, involving reduction in cell proliferation, extracellular matrix deposition, angiogenesis, mechanical signaling, as well as induction of apoptosis. Mifepristone and ulipristal acetate may induce an antiendometriosis effect through modulation of cell proliferation, apoptosis, and adhesion. Mifepristone also may induce inhibitory effects on endometrial cancer by downregulation of cell proliferation and upregulation of apoptosis. Three SPRMs, including mifepristone, telapristone acetate, and ulipristal acetate, are thought to exert a therapeutic effect on breast cancer, at least in part, by downregulation of cell proliferation, angiogenesis, and migration, as well as the induction of apoptosis.