Selective estrogen receptor modulator

Selective estrogen receptor modulators (SERMs), also known as estrogen receptor agonist/antagonists (ERAAs),

Medical uses

SERMs are used for various estrogen-related diseases, including treatment of ovulatory dysfunction in the management of infertility, treatment and prevention of postmenopausal osteoporosis, treatment and reduction in risk of breast cancer^[4] and treatment of dyspareunia due to menopause. SERM is also used in combination with conjugated estrogens indicated for the treatment of estrogen deficiency symptoms, and vasomotor symptoms associated with menopause.^[5] SERMs are used dependent on their pattern of action in various tissues:

Bazedoxifene is used as treatment for osteoporosis in postmenopausal women at increased risk of fracture. It has been shown to be relatively safe and well tolerated. It shows no breast or endometrial stimulation and in the first two years, the small increase is better in venous thromboembolism, and similar in the long term to other SERMs. The advantage of bazedoxifene over raloxifene is that it increases endothelial nitric oxide synthase activity and does not antagonize the effect of 17β-estradiol on vasomotor symptoms.^[5]

The first tissue selective estrogen complex (TSEC) combines conjugated estrogens and the SERM bazedoxifene to blend their activities. The combination therapy is used in the treatment of moderate to severe vasomotor symptoms associated with menopause, prevention of postmenopausal osteoporosis as well as treatment of estrogen deficiency symptoms in non-hysterectomized postmenopausal women. The combination allows for the benefits of estrogen with regard to relief of vasomotor symptoms without estrogenic stimulation of the endometrium.^[5][6]

SERMs have also been used as a hormonal treatment option by some transgender people.^[8]

Available forms

Pharmacology

Pharmacodynamics

SERMs are competitive

SERM act on the estrogen receptor (ER), which is an

• Full agonists (agonistic in all tissues) such as the natural endogenous hormone estradiol
• Mixed agonists/antagonistics (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.^[19] This agonistic or antagonistic activity causes varied structural changes of the receptors, which results in activation or repression of the estrogen target genes.^{[3][19][4][20]} SERMs interact with receptors by diffusing into cells and there binding to ERα or ERβ subunits, which results in 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.^[19]

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.

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.[4] However, the external shape of the resulting complex is what becomes the catalyst for changing the response at a tissue target to a SERM.^{[3][19][4][20]}

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.[4]

Structure and function

Structure–activity relationships

The core structure of SERMs simulates the

The first main structural class of SERM-type molecules reported are the triphenylethylenes. The stilbene core (similar to the nonsteroidal estrogen, diethylstilbestrol) essentially mimics steroidal estrogens such as 17β-estradiol, while the side chain overlays with the 11th position of the steroid nucleus.^[7] Triphenylethylene derivatives have an additional phenyl group attached to the ethylene bridge group. The 3-position H-bonding ability of phenols is a significant requirement for ER binding.^[22]

The first drug, clomifene,

Tamoxifen has become the treatment of choice for women diagnosed with all stages of hormone-responsive breast cancer, that is, breast cancer that is both ER and/or progesterone positive. In the US, it is also administered for prophylactic chemoprevention in women identified as high risk for breast cancer.

The crystallographic structure of 4-hydroxytamoxifen[26] interacts with the amino acids of the ER within the ligand-binding domain.^[27] The contact between the phenolic group, water molecule, and glutamate and arginine in the receptor (ERα; Glu 353/Arg 394) resolves in high affinity binding so that 4-hydroxy tamoxifen, with a phenolic ring that resembles the A ring of 17β-estradiol, has more than 100 times higher relative binding affinity than tamoxifen, which has no phenol. If its OH group is eliminated or its position is changed the binding affinity is reduced.^[7][22]

The triphenylethylene moiety and the side chain are required for tamoxifen binding to the ER, whereas for 4-hydroxytamoxifen, the side chain, and the phenyl-propene do not appear as crucial structural elements for binding to the ER. The

Toremifene is a chlorinated derivative of the nonsteroidal triphenylethylene antiestrogen tamoxifen

Raloxifene belongs to the second-generation

The advantage of raloxifene over the triphenylethylene tamoxifen is reduced effect on the uterus. The flexible hinge group, as well as the antiestrogenic phenyl 4-piperidinoethoxy side chain, are important for minimizing uterine effects. Because of its flexibility the side chain can obtain an orthogonal disposition relative to the core[7] so that the amine of raloxifens side chain is 1 Å closer than tamoxifens to amino acid Asp-351 in ERα's ligand-binding domain.^[24][29]

The critical role of the intimate relationship between the hydrophobic side chain of raloxifene and the hydrophobic residue of the receptor to change both the shape and charge of the external surface of a SERM-ER complex has been confirmed with raloxifene derivatives. When the interactive distance between raloxifene and Asp-351 is increased from 2.7 Å to 3.5-5 Å it causes increased estrogen-like action of the raloxifene-ERα complex. When the piperidine ring of raloxifene is replaced by cyclohexane, the ligand loses antiestrogenic properties and becomes a full agonist. The interaction between SERM's antiestrogenic side chain and amino acid Asp-351 is the important first step in silencing AF-2. It relocates helix 12 away from the ligand-binding pocket thereby preventing coactivators from binding to the SERM-ER complex.^[24][29]

Third-generation

Third-generation compounds display either no uterine stimulation, improved potency, no significant increases in hot flushes or even a combination of these positive attributes.^[7]

The first dihydronapthalene SERM, nafoxidine, was a clinical candidate for the treatment of breast cancer but had side effects including severe phototoxicity. Nafoxidine has all three phenyls constrained in a coplanar arrangement like tamoxifen. But with hydrogenation, the double bond of nafoxidene were reduced, and both phenyls are cis-oriented. The amine-bearing side chain can then adopt an axial conformation and locate this group orthogonally to the plane of the core, like ralofoxifene and other less uterotropic SERMs.

Modifications of nafoxidine resulted in lasofoxifene. Lasofoxifene is among the most potent SERMs reported in protection against bone loss and cholesterol reduction. The excellent oral potency of lasofoxifene has been attributed to reduced intestinal glucuronidation of the phenol.^[7] Unlike raloxifene, lasofoxifene satisfies the requirement of a pharmacophore model that predicts resistance to gut wall glucuronidation. The structural requirement is a non-planar topology with the steric bulk close to the plane of a fused bicyclic aromatic system.^[30] The interactions between the ER and lasofoxifene are consistent with the general features of SERM-ER recognition. Lasofoxifene's large flexible side chain terminates in a pyrrolidine head group and threads its way out toward the surface of the protein, where it interferes directly with the positioning of the AF-2 helix. A salt bridge forms between lasofoxifene and Asp-351. The charge neutralization in this region ER may explain some antiestrogenic effects exerted by lasofoxifene.^[12]

The indole system has served as a core unit in SERMs, and when an amine is attached to the indole with a benzyloxyethyl, the resultant compounds were shown to have no preclinical uterine activity while sparing rat bone with full efficacy at low doses. Bazedoxifene is one of those compounds. The core binding domain consists of a 2-phenyl-3-methyl indole and a hexamethylenamine ring at the side chain affecter region. It is metabolized by glucuronidation, with the absolute bioavailability of 6.2%, 3-fold higher than that of raloxifene. It has agonistic effects on bone and lipid metabolism but not on breast and uterine endometrium.^[31] It is well tolerated and displays no increase in hot flush incidences,^[spelling?] uterine hypertrophy or breast tenderness.^[7]

Ospemifene is a triphenylethylene and a known metabolite of toremifene. It's structurally very similar to tamoxifen and toremifene. Ospemifene does not have 2-(dimethylamino)ethoxy group as tamoxifen. Structure–activity relationship studies showed that by removing that group of tamoxifen agonistic activity in the uterus was significantly reduced, but not in bone and cardiovascular system. Preclinical and clinical data show that ospemifene is well tolerated with no major side effects. Benefits that ospemifene may have over other SERMs is its neutral effect on hot flushes and ER-agonist effect on the vagina, improving the symptoms of vaginal dryness.^[32]

Binding modes

The SERMs are known to feature four distinctive modes of binding to ER. One of those features are strong

The small differences between the two subtypes of ER have been used to develop subtype-selective ER modulators, but the high similarity between the two receptors make the development very challenging. Amino acids in the ligand-binding domains differ at two positions, Leu-384 and Met-421 in ERα and Met-336 and Ile-373 in ERβ, but they have similar hydrophobicity and occupying volumes. However, the shapes and the rotational barrier of the amino acid residues are not the same, leading to distinguish α- and β-face of the binding cavity between ERα and ERβ. This causes ERα-preferential-binding of ligand substituents that are aligned downwards facing Met-336 while ligand substituents aligned upwards facing Met-336 are more likely to bind to ERβ. Another difference is in Val-392 in ERα, which is replaced by Met-344 in ERβ. ERβ's binding pocket volume is slightly smaller and the shape a bit different from ERα's. Many ERβ-selective ligands have a largely planar arrangement as the binding cavity of ERβ is slightly narrower than that of ERα, however, this by itself leads to modest selectivity. To attain strong selectivity, the ligand must place substituents very close to one or more of the amino acid differences between ERα and ERβ in order to create a strong repulsive force towards the other subtype receptor. In addition, the structure of the ligand must be rigid. Repulsive interactions may otherwise lead to conformational change of the ligand and, therefore, creating alternative binding modes.^[13]

First-generation triphenylethylenes

Tamoxifen is converted by the liver cytochrome P450 into the 4-hydroxytamoxifen^[12] and is a more selective antagonist of the ERα subtype than ERβ.^[33] 4-hydroxytamoxifen binds to ERs within the same binding pocket that recognizes 17β-estradiol. The receptor recognition of 4-hydroxytamoxifen appears to be controlled by two structural features of 4-hydroxytamoxifen, the phenolic A ring, and the bulky side chain. The phenolic A ring forms hydrogen bonds to the side groups of ER's Arg-394, Glu-354 and to structurally conserved water. The bulky side chain, protruding from the binding cavity, displaces helix 12 from ligand-binding pocket to cover part of the coactivator binding pocket. The ER-4-hydroxytamoxifen complex formation recruits corepressors proteins. This leads to decreased DNA synthesis and inhibition of estrogen activity.^[12] Clomifene and torimefene produce binding affinities similar to that of tamoxifen.^[22] Thus, these two drugs are more selective antagonists of the ERα subtype than ERβ.^[33]

Second-generation benzothiophenes

Raloxifene, like 4-hydroxytamoxifen, binds to ERα with the hydroxyl group of its phenolic "A ring" through hydrogen bonds with Arg-394 and Glu-353. In addition to these bonds, raloxifene forms a second hydrogen bond to ER through the side group of His-524 because of the presence of a second hydroxyl group in the "D ring". This hydrogen bond is also unlike that between 17β-estradiol and His-524, as the

Lasofoxifene interaction with ERα is typical of those between SERM-ERα such as a nearly planar topology (the tetrahydronapthalene carbocycle), hydrogen bonding with Arg-394 and Glu-353 and the phenyl side chains of lasofoxifene filling the C-ring and D-ring volume of the ligand-binding pocket. Lasofoxifene diverts helix 12 and prevents the binding of coactivator proteins with LXXLL motives. This is achieved by lasofoxifene occupying the space normally filled by Leu-540's side group and modulating the conformation of residues of helix 11 (His-524, Leu-525). Furthermore, lasofoxifene also directly interferes with helix 12 positioning by the drug's ethyl pyrrolidine group.^[12] In vitro studies indicate that bazedoxifene competitively blocks 17β-estradiol by high and similar binding to both ERα and ERβ.^[34] Bazedoxifenes main binding domain consists of the 2-phenyl-3-methylindole and a hexamethylenamine ring at the side chain affected region.^[31]

Ospemifene is an oxidative deaminated metabolite of toremifene as has a similar binding to ER as toremifene and tamoxifen. The competitive binding to ERα and ERβ of the three metabolites 4-hydroxy Ospemifene, 4'-hydroxy Ospemifene and the 4-hydroxy-, side chain carboxylic acid Ospemifene is at least as high as the parent compound.^[35]

History

The discovery of SERMs resulted from attempts to develop new contraceptives.

It was another ten years before tamoxifen was approved in December 1977, not as a contraceptive but as a hormonal treatment to treat and prevent breast cancer.[6] The discovery in 1987 that the SERMs tamoxifen and raloxifene, then thought to be antiestrogens because of antagonist effects in breast tissue, showed estrogenic effects in preventing bone loss in ovariectomized rats had a great effect on our understanding of the function of estrogen receptors and nuclear receptors in general.^[7] The term SERM was introduced to describe these compounds that have a combination of estrogen agonist, partial agonist, or antagonist activities depending on the tissue.^[5] Toremifene has been shown to be compatible with tamoxifen, and in 1996 it was approved for use in the treatment of breast cancer in postmenopausal women.^[36]

Raloxifene originally failed as a breast cancer drug due to its poor performance in comparison to tamoxifen in the laboratory

• Estrogen deprivation therapy
• List of selective estrogen receptor modulators
• Selective androgen receptor modulator
• Selective estrogen receptor degrader
• Selective receptor modulator
• Timeline of cancer treatment development

References

External links

Wikimedia Commons has media related to Selective estrogen receptor modulators.

• AACR Cancer Concepts Factsheet on SERMs
• STAR: a head-to-head comparison of tamoxifen and raloxifene as breast-cancer preventatives
• Femarelle official site
• Raloxifene (Evista) official site