Editing Selective estrogen receptor modulator (section)

== Pharmacology ==

=== Pharmacodynamics ===

SERMs are competitive partial agonists of the ER.<ref name="CameronCameron2013">{{cite book | first1 = John L. | last1 = Cameron | first2 = Andrew M | last2 = Cameron | name-list-style = vanc | title = Current Surgical Therapy | url = https://books.google.com/books?id=QwYyAgAAQBAJ&pg=PA582|date=20 November 2013|publisher=Elsevier Health Sciences|isbn=978-0-323-22511-3|pages=582–}}</ref> Different tissues have different degrees of sensitivity to the activity of endogenous estrogens, so SERMs produce estrogenic or [[antiestrogen]]ic effects depending on the tissue in question, as well as the percentage of [[intrinsic activity]] (IA) of the SERM.<ref name="Huang_Aslanian_2012">{{cite book | first1 = Xianhai | last1 = Huang | first2 = Robert G. | last2 = Aslanian | name-list-style = vanc | title = Case Studies in Modern Drug Discovery and Development|url=https://books.google.com/books?id=MvsSTJigQcMC&pg=PA392|date=19 April 2012|publisher=John Wiley & Sons|isbn=978-1-118-21967-6|pages=392–394}}</ref> An example of a SERM with high IA and thus mostly estrogenic effects is [[chlorotrianisene]], while an example of a SERM with low IA and thus mostly antiestrogenic effects is [[ethamoxytriphetol]]. SERMs like [[clomifene]] and [[tamoxifen]] are comparatively more in the middle in their IA and their balance of estrogenic and antiestrogenic activity. [[Raloxifene]] is a SERM that is more antiestrogenic than tamoxifen; both are estrogenic in bone, but raloxifene is antiestrogenic in the [[uterus]] while tamoxifen is estrogenic in this part of the body.<ref name="Huang_Aslanian_2012" />

{{Tissue-specific estrogenic and antiestrogenic activity of SERMs}}

{{Affinities of estrogen receptor ligands for the ERα and ERβ}}

==== Binding site ====
{{See also|Estrogen receptor}}
[[Image:Er domains.svg| thumb| 400px|class=skin-invert-image|The domain structures of ERα and ERβ, including some of the known phosphorylation sites involved in ligand-independent regulation.]]

SERM act on the estrogen receptor (ER), which is an [[intracellular]], ligand-dependent [[transcriptional activator]] and belongs to the [[nuclear receptor]] family.<ref name="Kremoser_2007">{{cite journal | vauthors = Kremoser C, Albers M, Burris TP, Deuschle U, Koegl M | title = Panning for SNuRMs: using cofactor profiling for the rational discovery of selective nuclear receptor modulators | journal = Drug Discovery Today | volume = 12 | issue = 19–20 | pages = 860–9 | date = Oct 2007 | pmid = 17933688 | doi = 10.1016/j.drudis.2007.07.025 }}</ref> Two different subtypes of ER have been identified, [[Estrogen receptor alpha|ERα]] and [[Estrogen receptor beta|ERβ]]. ERα is considered the main medium where estrogen signals are [[Transduction (genetics)|transduced]] at the transcriptional level and is the predominant ER in the female reproductive tract and mammary glands while ERβ is primarily in vascular [[endothelial cells]], bone, and male prostate tissue.<ref name="Rosano_2011"/> ERα and ERβ concentration are known to be different in tissues during development, aging or disease state.<ref name="Nilsson_2011">{{cite journal | vauthors = Nilsson S, Koehler KF, Gustafsson JÅ | title = Development of subtype-selective oestrogen receptor-based therapeutics | journal = Nature Reviews. Drug Discovery | volume = 10 | issue = 10 | pages = 778–92 | date = Oct 2011 | pmid = 21921919 | doi = 10.1038/nrd3551 | s2cid = 23043739 }}</ref> Many characteristics are similar between these two types such as size (~600 and 530 [[amino acid]]s) and structure. ERα and ERβ share approximately 97% of the amino-acid sequence identity in the [[DNA-binding domain]] and about 56% in the [[ligand-binding domain]].<ref name="Kremoser_2007" /><ref name="Nilsson_2011" /> The main difference of the ligand-binding domains is determined by [[Leucine|Leu]]-384 and [[Methionine|Met]]-421 in ERα, which are replaced by Met-336 and [[Isoleucine|Ile]]-373, respectively, in ERβ.<ref name="Koehler_2005">{{cite journal | vauthors = Koehler KF, Helguero LA, Haldosén LA, Warner M, Gustafsson JA | title = Reflections on the discovery and significance of estrogen receptor beta | journal = Endocrine Reviews | volume = 26 | issue = 3 | pages = 465–78 | date = May 2005 | pmid = 15857973 | doi = 10.1210/er.2004-0027 | doi-access = free }}</ref> The variation is greater on the N-terminus between ERα and ERβ.<ref name="Duterte_2000">{{cite journal | vauthors = Dutertre M, Smith CL | title = Molecular mechanisms of selective estrogen receptor modulator (SERM) action | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 295 | issue = 2 | pages = 431–7 | date = Nov 2000 | doi = 10.1016/S0022-3565(24)38923-2 | pmid = 11046073 | url = http://jpet.aspetjournals.org/content/295/2/431.short | url-access = subscription }}</ref>

DNA-binding domain consists of two subdomains. One with a proximal box that is involved in DNA recognition while the other contains a distal box responsible for DNA-dependent, DNA-binding domain [[Dimer (chemistry)|dimerization]]. The proximal box sequence is identical between ERα and ERβ, which indicates similar specificity and affinity between the two subgroups. DNA-binding domain's globular proteins contain eight [[cysteine]]s and allow for a tetrahedral coordination of two [[zinc]] ions. This coordination makes the binding of ER to estrogen response elements possible.<ref name="Rosano_2011" /> The ligand-binding domain is a globular, three-layered structure made of 11 [[helix]]es and contains a pocket for the natural or synthetic ligand.<ref name="Rosano_2011" /><ref name="Kremoser_2007" /> Influencing factors for binding affinity are mainly the presence of a [[phenol]] moiety, molecular size and shape, double bonds and [[hydrophobicity]].<ref name="Xu_2010">{{cite journal | vauthors = Xu X, Yang W, Li Y, Wang Y | title = Discovery of estrogen receptor modulators: a review of virtual screening and SAR efforts | journal = Expert Opinion on Drug Discovery | volume = 5 | issue = 1 | pages = 21–31 | date = Jan 2010 | pmid = 22823969 | doi = 10.1517/17460440903490395 | s2cid = 207492889 }}</ref>

The differential positioning of the activating function 2 (AF-2) helix 12 in the ligand-binding domain by the bound ligand determines whether the ligand has an agonistic and antagonistic effect. In agonist-bound receptors, helix 12 is positioned adjacent to helices 3 and 5. Helices 3, 5, and 12 together form a binding surface for an NR box motif contained in [[Coactivator (genetics)|coactivators]] with the [[Consensus sequence|canonical sequence]] LXXLL (where L represents [[leucine]] or [[isoleucine]] and X is any amino acid). Unliganded (apo) receptors or receptors bound to antagonist ligands turn helix 12 away from the LXXLL-binding surface that leads to preferential binding of a longer leucine-rich motif, LXXXIXXX(I/L), present on the [[corepressor]]s NCoR1 or SMRT. In addition, some [[Cofactors and coenzymes|cofactors]] bind to ER through the terminals, the DNA-binding site or other binding sites. Thus, one compound can be an ER agonist in a tissue rich in [[Coactivator (genetics)|coactivators]] but an ER antagonist in tissues rich in [[Co-repressor|corepressors]].<ref name="Kremoser_2007" />

=== Mechanism of action ===
[[Image:NR mechanism.png| thumb| 480px| Structural basis for the mechanism of estrogen receptor agonist and antagonist action.<ref name = "Brzozowski_1997">{{cite journal | vauthors = Brzozowski AM, Pike AC, Dauter Z, Hubbard RE, Bonn T, Engström O, Öhman L, Greene GL, Gustafsson JÅ, Carlquist M | title = Molecular basis of agonism and antagonism in the oestrogen receptor | journal = Nature | volume = 389 | issue = 6652 | pages = 753–8 | year = 1997 | doi = 10.1038/39645 | pmid = 9338790 | bibcode = 1997Natur.389..753B | s2cid = 4430999 }}</ref> The structures shown here are of the ligand binding domain (LBD) of the estrogen receptor (green cartoon diagram) complexed with either the agonist [[diethylstilbestrol]] (top, {{PDB|3ERD}}) or antagonist [[4-hydroxytamoxifen]] (bottom, {{PDB2|3ERT}}). The ligands are depicted as space filling spheres (white = carbon, red = oxygen). When an agonist is bound to a nuclear receptor, the C-terminal [[alpha helix]] of the LBD (H12; light blue) is positioned such that a [[coactivator (genetics)|coactivator]] protein (red) can bind to the surface of the LBD. Shown here is just a small part of the coactivator protein, the so-called NR box containing the LXXLL amino acid sequence motif.<ref name = "Shiau_1998">{{cite journal | vauthors = Shiau AK, Barstad D, Loria PM, Cheng L, Kushner PJ, Agard DA, Greene GL | title = The structural basis of estrogen receptor/coactivator recognition and the antagonism of this interaction by tamoxifen | journal = Cell | volume = 95 | issue = 7 | pages = 927–37 | year = 1998 | doi = 10.1016/S0092-8674(00)81717-1 | pmid = 9875847 | s2cid = 10265320 | doi-access = free }}</ref> Antagonists occupy the same ligand binding cavity of the nuclear receptor. However antagonist ligands in addition have a sidechain extension which [[steric effects|sterically]] displaces H12 to occupy roughly the same position in space as coactivators bind. Hence coactivator binding to the LBD is blocked.]]

Estrogenic compounds span a spectrum of activity, including:{{cn|date=January 2025}}
* Full agonists (agonistic in all tissues), such as the natural endogenous hormone [[estradiol]].
* Mixed agonists/antagonistic (agonistic in some tissues while antagonistic in others), such as tamoxifen (a SERM).
* Pure antagonists (antagonistic in all tissues), such as [[fulvestrant]].

SERMs are known to stimulate estrogenic actions in tissues such as the liver, bone and cardiovascular system but known to block estrogen action where stimulation is not desirable, such as in the breast and the uterus.<ref name="Musa_2007"/> This agonistic or antagonistic activity causes varied structural changes of the receptors, which results in activation or repression of the estrogen target genes.<ref name="Riggs_2003"/><ref name="Musa_2007" /><ref name="Maximov_2013"/><ref name="Lewis_2005">{{cite journal | vauthors = Lewis JS, Jordan VC | title = Selective estrogen receptor modulators (SERMs): mechanisms of anticarcinogenesis and drug resistance | journal = Mutation Research | volume = 591 | issue = 1–2 | pages = 247–63 | date = Dec 2005 | pmid = 16083919 | doi = 10.1016/j.mrfmmm.2005.02.028 | bibcode = 2005MRFMM.591..247L }}</ref> SERMs interact with receptors by diffusing into cells and their binding to ERα or ERβ subunits, which results in [[Protein dimer|dimerization]] and structural changes of the receptors. This makes it easier for the SERMs to interact with estrogen response elements which leads to the activation of estrogen-inducible genes and mediating the estrogen effects.<ref name="Musa_2007" />

SERMs unique feature is their tissue- and cell-selective activity. There is growing evidence to support that SERM activity is mainly determined by selective recruitment of corepressors and coactivators to ER target genes in specific types of tissues and cells.<ref name="Maximov_2013" /><ref name="Lewis_2005" /><ref name="Feng_2014">{{cite journal | vauthors = Feng Q, O'Malley BW | title = Nuclear receptor modulation--role of coregulators in selective estrogen receptor modulator (SERM) actions | journal = Steroids | volume = 90 | pages = 39–43 | date = Nov 2014 | pmid = 24945111 | doi = 10.1016/j.steroids.2014.06.008 | pmc=4192004}}</ref> SERMs can impact coactivator protein stability and can also regulate coactivator activity through [[post-translational modification]]s such as [[phosphorylation]]. Multiple growth signaling pathways, such as [[HER2]], [[Protein kinase C|PKC]], [[PI3K]] and more, are [[Downregulation|downregulated]] in response to anti-estrogen treatment. Steroid receptor coactivator 3 (SRC-3) is phosphorylated by activated [[kinase]]s that also enhance its coactivator activity, affect cell growth and ultimately contribute to drug resistance.<ref name="Feng_2014" />

The ratio of ERα and ERβ at a target site may be another way SERM activity is determined. High levels of cellular proliferation correlate well with a high ERα:ERβ ratio, but repression of cellular proliferation correlates to ERβ being dominant over ERα. The ratio of ERs in [[Neoplasm|neoplastic]] and normal breast tissue could be important when considering [[chemoprevention]] with SERMs.<ref name="Riggs_2003" /><ref name="Musa_2007" /><ref name="Maximov_2013" /><ref name="Lewis_2005" />

When looking at the differences between ERα and ERβ, Activating Function 1 (AF-1) and AF-2 are important. Together they play an important part in the interaction with other co-regulatory proteins that control [[gene transcription]].<ref name="Musa_2007" /><ref name="Maximov_2013" /> AF-1 is located in the [[amino terminus]] of the ER and is only 20% homologous in ERα and ERβ. On the other hand, AF-2 is very similar in ERα and ERβ, and only one amino acid is different.<ref name="Maximov_2013" /> Studies have shown that by switching AF-1 regions in ERα and ERβ, that there are specific differences in transcription activity. Generally, SERMs can partially activate engineered genes through ERα by an estrogen receptor element, but not through ERβ.<ref name="Musa_2007" /><ref name="Maximov_2013" /><ref name="Lewis_2005" /> Although, raloxifene and the active form of tamoxifen can stimulate AF-1-regulated reporter genes in both ERα and ERβ.<ref name="Maximov_2013" />

Because of the discovery that there are two ER subtypes, it has brought about the synthesis of a range of receptor specific ligands that can switch on or off a particular receptor.<ref name="Maximov_2013" /> However, the external shape of the resulting complex is what becomes the catalyst for changing the response at a tissue target to a SERM.<ref name="Riggs_2003" /><ref name="Musa_2007" /><ref name="Maximov_2013" /><ref name="Lewis_2005" />

[[X-ray crystallography]] of estrogens or antiestrogens has shown how ligands program the receptor complex to interact with other proteins. The ligand-binding domain of the ER demonstrates how ligands promote and prevent coactivator binding based on the shape of the estrogen or antiestrogen complex. The broad range of ligands that bind to the ER can create a spectrum of ER complexes that are fully estrogenic or antiestrogenic at a specific target site.<ref name="Riggs_2003" /><ref name="Maximov_2013" /><ref name="Lewis_2005" /> The main result of a ligand-binding to ER is a structural rearrangement of the ligand-[[Active site|binding pocket]], primarily in the AF-2 of the C-terminal region. The binding of ligands to ER leads to the formation of a [[hydrophobic]] pocket that regulates cofactors and receptor pharmacology. The correct [[Protein folding|folding]] of ligand-binding domain is required for activation of transcription and for ER to interact with a number of coactivators.<ref name="Maximov_2013" />

Coactivators are not just protein partners that connect sites together in a complex. Coactivators play an active role in modifying the activity of a complex. Post-translation modification of coactivators can result in a dynamic model of [[steroid hormone]] action by way of multiple kinase pathways initiated by cell surface [[growth factor receptor]]s. Under the guidance of a multitude of protein remodelers to form a multiprotein coactivator complex that can interact with the phosphorylated ER at a specific gene promoter site, the core coactivator first has to recruit a specific set of cocoactivators. The proteins that the core coactivator assembles as the core coactivated complex have individual enzymatic activities to [[Methylation|methylate]] or [[Acetylation|acetylate]] adjacent proteins. The ER substrates or [[coenzyme A]] can be [[Polyubiquitination|polyubiquitinated]] by multiple cycles of the reaction or, depending on linkage proteins, they can either be activated further or degraded by the [[26S proteasome]].<ref name="Maximov_2013" />

Consequently, to have an effective gene transcription that is programmed and targeted by the structure and phosphorylation status of the ER and coactivators, it is required to have a dynamic and cyclic process of remodeling capacity for transcriptional assembly, after which the transcription complex is then instantly routinely destroyed by the proteasome.<ref name="Maximov_2013" />