Selective progesterone receptor modulator
A selective progesterone receptor modulator (SPRM) is an agent that acts on the progesterone receptor. A characteristic that distinguishes such substances from receptor full agonists (such as progesterone) and full antagonists (such as aglepristone) is that their action differs in different tissues (agonist in some while antagonist in others). This mixed agonist/antagonist profile of action leads to selective stimulation or inhibition progesterone-like action in different tissues and furthermore raises the possibility of dissociation of desirable therapeutic effects from undesirable side effects in synthetic progesterone receptor drug candidates.
- Ulipristal acetate ("Ella")
- Asoprisnil (J867; status uncertain)
- Telapristone (CDB-4124; Proellex, Progenta; under development)
SPRMs are under development for the following uses:
- Asoprisnil and CDB-4124 are both under investigation (2005) for the medical treatment of uterine leiomyoma.
- Proellex has completed a number of clinical trials to treat endometriosis and uterine fibroids.
While these SPRMs have been effective for the treatment of uterine fibroids, development of side effects such as endometrial thickening has limited their administration to no longer than three to four months.
Mechanism of action
Synthetic SPRMs differ in chemical structure from the endogenous hormone progesterone, but nevertheless bind to the same progesterone receptor. In humans, there is only one gene (PGR) that codes for the receptor, but two splice variants (PR-A and -B) arising from this single gene each with a somewhat different tissue distribution and intrinsic functional activity in response to ligand binding (agonist vs. antagonist). In addition, synthetic SPRMs may have some binding selectivity between the two isoforms, although this is unlikely as the ligand binding domains of the two isoforms are identical.
A more likely origin of the tissue selectivity of SPRMs is what conformational preference these ligands induce in the receptor. The ligand binding domain of the receptor is in equilibrium between two different conformations. The first is an agonist conformation which favors the binding of coactivator proteins which in turn favors upregulation of gene transcription. The second is an antagonistic conformation which in contrast favors the binding of corepressors and as a consequence down regulation of gene expression. Full agonists such as progesterone which display agonist properties in all tissues, strongly shift the conformational equilibrium in the agonist direction. Conversely full antagonists such as aglepristone strongly shift the equilibrium in the antagonist direction. Finally, the overall ratio of concentrations of coactivator to corepressor may differ in different cell types.
When SPRMs bind to the progesterone receptor, the equilibrium between the two conformational states is more closely balanced and hence more easily perturbed by differences in the cellular environment. In tissues where the concentration of coactivators is higher than corepressors, the excess coactivators drive the equilibrium in the agonist direction. Conversely in tissues where corepressor concentration is higher the equilibrium is driven in the antagonist direction. Hence SPRMs display agonist activity in tissues where coactivators predominate and antagonist activity where corepressors are in excess.
- Selective receptor modulator
- Selective androgen receptor modulator
- Selective estrogen receptor modulator
- Selective glucocorticoid receptor agonist
- Chwalisz K, Perez MC, Demanno D, Winkel C, Schubert G, Elger W (2005). "Selective progesterone receptor modulator development and use in the treatment of leiomyomata and endometriosis". Endocr Rev 26 (3): 423–38. doi:10.1210/er.2005-0001. PMID 15857972.
- Ohara N (2008). "Action of progesterone receptor modulators on uterine leiomyomas". Clin Exp Obstet Gynecol 35 (3): 165–6. PMID 18754282.
- Spitz IM (August 2009). "Clinical utility of progesterone receptor modulators and their effect on the endometrium". Curr. Opin. Obstet. Gynecol. 21 (4): 318–24. doi:10.1097/GCO.0b013e32832e07e8. PMID 19602929.
- "Proellex Clinical Studies". ClinicalTrials.gov, United States National Institutes of Health. Retrieved 2010-07-03.
- Jackson TA, Richer JK, Bain DL, Takimoto GS, Tung L, Horwitz KB (1997). "The partial agonist activity of antagonist-occupied steroid receptors is controlled by a novel hinge domain-binding coactivator L7/SPA and the corepressors N-CoR or SMRT". Mol Endocrinol 11 (6): 693–705. doi:10.1210/me.11.6.693. PMID 9171233.
- Smith CL, O'Malley BW (2004). "Coregulator function: a key to understanding tissue specificity of selective receptor modulators". Endocr Rev 25 (1): 45–71. doi:10.1210/er.2003-0023. PMID 14769827.