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| The androgen receptor (AR) belongs to the steroid hormone group nuclear receptor family with the estrogen, progesterone, glucocorticoid and mineralcorticoid receptor.
| | == Human protein phosphatase 2C == |
| AR mediate the actions of testosterone (T) and a more biologically active form, 5α-dihydrotestosterone (DHT), which are the male sex hormones required for development of the male reproductive system and secondary sexual characteristics. This receptor, located on the X chromosome, is expressed in a diverse range of tissues, because they have significant biological actions in many systems <ref name="Bench to Bedside">PMID: 27057074</ref>. There are other androgens that bind with much less potency than T and DHT such as androstenedione, androstenediol, and dehydroepiandrosterone (DHEA) <ref>PMID: 36376977</ref>.
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| =Structure= | | <Structure load='2IQ1' size='350' frame='true' align='right' caption='Quartenary structure of human protein phosphatase PP2Cm with Mg(II) (PDB ID 4DA1)' scene='Insert optional scene name here' /> Protein Phosphatases 2C are essencial enzymes involved in the regulation of several signaling pathways of branched-chain α-ketoacid dehydrogenase complex (BCKDC) by phosphorylation/dephosphorylation. The PP2C Family are Mg<sup>2+</sup> and Mn<sup>2+</sup> dependent monomeric proteins with two characteristic structural domains: a catalytic domain N-terminal with six alpha-helices, and a C-terminal region with three alpha-helices. The multienzyme complex uses numerous copies of three enzymes as major building blocks E1, E2 and E3. A dihydrolipoyl transacylase (E2) forms the core of the complex with 24 copies in octahedral symmetry. |
| Like members of the nuclear receptor family, the AR consists of three main functional domains which aid in controlling and regulating transcriptional activity.
| | The human branched-chain α-ketoacid dehydrogenase complex ser/thr phosphatase, PP2Cm, (BDP) is attached to the E2 core through non-covalent bonds. PP2Cm is distinguished from other groups of phosphatases by its structural distinction, absolute requirement for divalent cation, the <scene name='32/32/Protein_pp2cm_with_mgii/7'>beta-sheet sandwich</scene> catalytic domain and shows Mn<sup>2+</sup>/Mg<sup>2+</sup> dependent phosphatase activity. PP2Cm structure has two central antiparallel beta sheets that are flanked by alpha helices and the <scene name='32/32/Protein_pp2cm_with_mgii/4'>active site</scene> is located at one end of the beta-sheet sandwich containing two <scene name='32/32/Protein_pp2cm_with_mgii/6'>magnesium ions</scene> coordenated by <scene name='32/32/Protein_pp2cm_with_mgii/5'>Asp-109, Asp-208, Asp-298, and Asp-337</scene> residues. |
| ==Domains==
| | At high levels of branched-chain ketoacids PP2Cm dephosphorylates Ser-337 and activates mitochondrial BCKDC complex by associating with the E2 component of the complex. |
| ===N-terminal Domain (NTD)(residues 1-555)===
| | The water molecules at the binuclear metal centre coordinate the phosphate group of the substrate, each ion is hexa-coordinated by <scene name='32/32/Protein_pp2cm_with_mgii/8'>oxygen atoms</scene> from water, providing a nucleophile and general acid in the dephosphorylation reaction, and Arg33 creates a local positive electrostatic potential on the protein for recognition of the phosphate group of the substrate. The nucleophile is the metal-bridging water molecule which could attack the phosphorus atom in an S<sub>N</sub>2 mechanism. Coordination to two Mg<sup>2+</sup> ions may stabilize the morenucleophilic hydroxide ion species. Other ions such as Ca<sup>2+</sup>, Zn<sup>2+</sup> and Ni<sup>2+</sup> inactivate the enzyme by competitively inhibiting Mn<sup>2+</sup> or Mg<sup>2+</sup> binding. |
| This region is required for full transcriptional activity <ref name="Structure">PMID: 24909511</ref>, because of its necessary presence for LBD activation <ref name="AR">PMID: 33076388</ref>. It is the most variable domain, the sequence and lengths of the polyglutamine (CAG) and polyglycine (GGC) repeats are highly variable in the human population. It has been shown that the length of the polyglutamine repeat region affects the folding and structure of this domain, shorter repeats generally impose a higher AR transactivation activity, whereas longer repeats cause reduced activity <ref name="Structure" />. In healthy people, one region of the AR gene shows up to 36 repeats of the CAG sequence. Patients with abnormally high numbers of CAG repeats can develop spinal muscular atrophy.
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| ===DNA-Binding Domain (DBD) (residues 555-623)=== | | == branched-chain α-ketoacid dehydrogenase complex == |
| DBD is a cysteine-rich region that is the most highly conserved one of the steroid hormone nuclear receptor family <ref name="Structure" />, but it has been shown that binding of selective androgen response elements (AREs) allow the specific activation functions of the AR. They facilitate direct DNA binding of the AR to the promoter and enhancer regions of AR-regulated genes, thereby allowing the activation functions of the N-terminal and ligand binding domains to stimulate or repress the transcription of these genes <ref name="Bench to Bedside" />.
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| AR is a dimer, like other steroid receptors, that binds to promoter DNA response elements consisting of two equal, common hexameric half-sites, separated by a 3 base-pair spacer <ref name="Structure" />'''IMAGEN DEL DÍMERO''', and this domain is critical for AR function, because it plays a role in dimerization and binding of dimerized AR to select motifs on target DNA <ref name="AR" />.
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| Each DBD monomer has a core composed of two zinc finger motifs, which consists of four cysteine residues that coordinate a zinc ion <ref name="Structure" />. The first is closer to the NTD which has the P box, which is identical in all the family, and controls the DNA binding specificity at AREs, located in the regulatory regions of genes <ref name="AR" />.
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| The second zinc finger motif facilitates AR dimerization via the D box. Additionally, a nuclear localization signal (NLS) is localized at the junction between the DBD and the hinge region and it binds to importin-α and facilitates nuclear translocation <ref name="AR" />. This is because passive transport across the nuclear pore complex has been suggested ranging from 20–40 kDa, in contrast, the AR, which is 110 kDa in size, requires help to be actively transported upon ligand binding <ref name="Structure" />.
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| The DBD is linked to the ligand binding domain by a flexible hinge region (residues 623-665), which is a linker poorly conserved. Once in the nucleus, this region also interacts with the DBD to identify specific sequences for AR binding. It controls the AR activation and degradation. Consequently, mutations in the hinge region can lead to enhanced AR potency <ref name="AR" />.
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| ===Ligand-Binding Domain (LBD) (residues 665-919)===
| | The human branched-chain α-ketoacid dehydrogenase (BCKD) complex is part of the mitochondrial α-ketoacid dehydrogenase complex family. Their structure consists of numerous copies of three enzymes E1, E2 and E3. A <scene name='32/32/E2b/1'> dihydrolipoyl transacylase (E2)</scene> forms the core |
| The LBD, located at the C-terminal, is the main target of AR inhibitors <ref name="AR" />. It consists of eleven α-helixes in the ligand binding pocket, with reposition upon androgen binding, converting into the activation function 2 (AF-2) domain. Unlike other nuclear receptors, the AR does not have H2, which is instead replaced by a long flexible linker <ref name="Structure" />. The LBD binds motifs in the NTD and in AR-specific cofactors and coactivators. Moreover, LBD-LBD homodimerization of AR is essential in the proper functioning of the receptos <ref name="AR" />.
| | of the complex with 24 copies in octahedral symmetry. Copies of the <scene name='32/32/E1/1'> α-ketoacid dehydrogenase (E1)</scene>, and copies of the<scene name='32/32/E3/2'> dihydrolipoamide dehydrogenase (E3)</scene>. In some types of (BCKDC) that are two regulatory enzymes proteins <scene name='32/32/Kinase/1'> protein kinase</scene> and <scene name='32/32/Phosphatase/1'> protein phosphatase</scene> that are attached to the E2 core through non-covalent bonds. |
| This domain has been structurally well characterized by crystallography and a number of mutations have been identified. It is important because not all mutations affect ligand binding, but some of them may disrupt androgen induced interaction of the N-terminal motif and C-terminal AF-2 <ref name="AR" />.
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| ==Transcriptional Activation Function== | | ==References, for further information on PP2Cm== |
| Two transcriptional activation functions have been identified:
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| -The ligand-independent AF-1 (residues 142-485): located in the NTD is constitutively active. It is the main region responsible for mediating AR transcription. This region contains two separable transcription activation units that are indispensable for full activity of the AR <ref name="Structure" />.
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| -The ligand-dependent AF-2: is located in the ligand binding domain <ref name="Bench to Bedside" />. <scene name='85/857155/H12_androgen_receptor/1'>H12</scene> forms the core of this region and acts as a lid to close the LBP upon agonist binding <ref name="Structure" />. It is important for forming the coregulator bindings site as well as mediating direct interactions between the N-terminal and ligand binding domains. Key differences in the contribution of specific conserved residues in the AF-2 core domain between the AR and other steroid hormone nuclear receptors have been identified, it would explain the differences in the structure and the function, as well as the coregulatory proteins they interact with <ref name="Bench to Bedside" />.
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| =Mechanism of Action=
| | * Ævarsson, A. ''et all'' "Crystal structure of human branched-chain α-ketoacid dehydrogenase and the molecular basis of multienzyme complex deficiency in maple syrup urine disease", CellPress. [https://www.sciencedirect.com/science/article/pii/S0969212600001052]. |
| ==AR signaling==
| | * Wynn, R. M. ''et all'' "Structure, function and assembly of mammalian branched-chain α-ketoacid dehydrogenase complex", Alpha-Keto Acid Dehydrogenase Complexes. [https://link.springer.com/chapter/10.1007/978-3-0348-8981-0_7] |
| AR has two mechanisms of action: the DNA binding-dependent (genomic AR signaling) and the DNA binding independent (non-genomic AR signaling).
| | * Lu, G. ''et all'' "Protein phosphatase 2Cm is a critical regulator of branched-chain amino acid catabolism in mice and cultured cells", The Journal of clinical investigation 119(6):1678-87. [https://www.researchgate.net/publication/24398300_Protein_phosphatase_2Cm_is_a_critical_regulator_of_branched-chain_amino_acid_catabolism_in_mice_and_cultured_cells]. |
| '''[[Image:Example.jpg]]''' | | * Pan, B. F ''et all'' "Regulation of PP2Cm expression by miRNA-204/211 and miRNA-22 in mouse and human cells [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4816230/] |
| ===DNA-Binding dependent actions of the AR===
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| In the absence of ligand, the AR is in the cytoplasm and associated with heat-shock and other chaperone proteins. Testosterone is converted into DHT by 5α-reductase, with higher affinity to bind AR. When DHT binds AR, it displaces heat shock proteins, drives the interaction between the N and C terminal, and binds importin-α to translocate the ligand/AR complex into the nucleus.
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| In the nucleus, the receptor dimerizes and binds to AREs in the promoter regions of target genes. At the promoter, the AR is able to recruit members of the basal transcription machinery in addition to other coregulators to facilitate transcription <ref name="Structure" />. AR activity is not only regulated by ligand binding and DNA binding but also by intramolecular interactions between functional domains, by homodimerization and by interactions with cofactors (4).
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| This leads to the initiation of transcription, cell proliferation and survival, and negative feedback to inactivate AR transcription <ref name="Bench to Bedside" />.
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| '''[[Image:Example.jpg]]'''
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| ===Non-DNA Binding dependent actions of the AR===
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| It has been shown that the androgen/AR complex activates 2nd messenger pathways including ERK, Akt and MAPK and that it interferes with several key proteins including forkhead box protein A1 (FOXA1), PI3K and receptor tyrosine kinases, including ERBB2 and ERBB3. These effects occur within seconds to minutes of androgen treatment <ref name="Bench to Bedside" /><ref>PMID: 28301631</ref>.
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| There are studies that suggest that some of the non-DNA binding-dependent actions of androgens are mediated via the activation of membrane-bound protein receptors. For instance, the iron-regulated transporter-like protein 9 (ZIP9) mediates the androgen-induced apoptosis of ovarian follicle cells, prostate and breast cancer cells <ref name="Bench to Bedside" />.
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| Although the physiological significance of the non-DNA binding-dependent actions of the AR is not yet fully defined, it has been proposed that they may oppose the DNA binding-dependent actions and serve as a brake to fine-tune androgen action in target tissues <ref name="Bench to Bedside" />.
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| ===Ligand-Independent actions of the AR===
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| It has been demonstrated that AR has the potential to be activated through ligand-independent mechanisms by a number of different growth factors, via phosphorylation of the AR or following interaction with co-activators <ref name="Bench to Bedside" />.
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| =Function=
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| AR is expressed in many tissues, so androgens have been documented to have significant biological actions in bone, muscle, prostate, ovaries, endometrium, bladder, skin, cardiovascular, immune, neural and hematopoietic systems <ref name="Bench to Bedside" /><ref name="Above and Beyond">PMID: 29481861</ref>.
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| Androgens have a role in behavior and cognition in neuronal cells in the CNS <ref name="Above and Beyond" />. It has also been shown they regulate hair growth, sebum production and secretion, wound healing and cutaneous barrier formation in the skin <ref>PMID: 28912032</ref>.
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| The absence of AR has an impact on the fertility in granulosa cells in the ovary and it also affects the myometrial cell growth in uterine glandular epithelial cells in the endometrium <ref name="Above and Beyond" />.
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| ==Diseases==
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| Drugs targeting the AR has the potential to be used in prostate cancer, benign prostatic hyperplasia (BPH), osteoporosis, breast cancer, hypogonadism, conditions where cachexia is a consequence of the disease state (HIV, cancer, immobilization), urinary incontinence, muscle wasting conditions as Duchenne muscular dystrophy (DMD) and Alzheimer’s disease <ref name="SARMs knowledge">PMID: 30503797</ref><ref name="NR">PMID: 23457206</ref><ref name="SARMs therapy">PMID: 32257854</ref><ref name="SARMs">PMID: 28624515</ref>.
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| ====Prostate Cancer====
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| Androgen receptor is fundamental for the correct function, development of the prostate <ref>PMID: 12237244</ref> having a critical role in the control of homeostasis between prostate cells differentiation and proliferation <ref name="ARA prostate">PMID: 24639562</ref>. It's widely accepted that androgen receptor plays an important role in prostate cancer cells due to the alteration of that equilibrium, shifting the AR to a more proliferative transcriptional program <ref name="ARA prostate” />.
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| ====Alzheimer’s Disease====
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| Androgen depletion is considered a significant risk factor for Alzheimer’s disease and circulating testosterone levels are inversely correlated with levels of ß-amyloid (ßA) in the brains of aged men <ref name="SARMs knowledge" />.
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| =Pharmacology=
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| ==Steroid==
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| ===Natural ligand: Testosterone===
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| Aging and other factors are associated with a reduction of testosterone levels which could lead to late onset hypogonadism <ref name="hypogonadism">PMID: 32737921</ref>. The decrease of the testosterone levels and therefore its active metabolite levels (DHT) are related with several symptoms such as low libido, erectile dysfunction, skeletal muscular loss <ref name="NR” /><ref name="hypogonadism" />, increased cardiovascular risk <ref name="hypogonadism" />… To treat those symptoms is used Testosterone Restitution Therapy (TRT) which has been associated with the improve in sexual function, increase in muscle mass and bone mineral density <ref name="Testosterone">PMID: 34888506</ref>.
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| One of the problems associated with the use of T as a therapeutic agent in TRT are the delivery method, tending to have low efficacy orally administered <ref name="NR” /><ref name="SARMs therapy” /> and having some inconvenients with intramuscular injections or implants <ref name="NR” />. Also, the use of this hormone as a treatment could triggered a lot of AR widespread around the body and a long-term exposure to a high dose could lead to related side effects like erythrocytosis <ref name="NR” /><ref name="SARMs therapy” />, dyslipidemia, hepatotoxicity <ref name="SARMs therapy” /> and in some clinical trials it has been described an increase in cardiovascular risk <ref name="Testosterone" /><ref name="hypogonadism" />.
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| Due to all these problems, some institutions like the FDA warn about the safety issues related with this therapy assessing the reduction of its use <ref name="Testosterone" /><ref name="hypogonadism" />. However, other agencies like the EMA supported by the European Academy of Andrology establish the practical use of this therapy in men’s hypogonadism <ref name="Testosterone" /><ref name="hypogonadism" />. So, there is still some controversy about its use, and it’s still currently studied in clinical trials <ref name="Testosterone" />.
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| ===Antagonist: Steroid ARA===
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| The development of these drugs were one of the first approaches to treat prostate cancer, targeting AR activity by having a structure with an steroidal skeleton <ref name="ARA prostate” />.
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| This kind of antiandrogens have another steroid receptor affinity (glucocorticoids receptor, progesterone receptor…) having low efficiency and some side effects like hepatotoxicity and increased cardiovascular risks <ref name="ARA prostate” />. Some examples are cyproterone acetate (CPA) <ref name="ARA prostate” /><ref name="bicalutamide">PMID: 15833816</ref><ref name="nonsteroidal">PMID: 16841196</ref> or megestrol acetate <ref name="ARA prostate” />.
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| ===Agonist: Anabolic Androgen Steroids (AAs)===
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| These drugs have been produced since the middle of the 20th century <ref name="Steroids">PMID: 33148520</ref>. They have anabolic activity which improves muscular mass and physical function. However, their uncontrolled use and abuse lead to several side effects like: testicular atrophy, alopecia, gynecomastia in the case of males, and clitoral hypertrophy, menstrual irregularities in the case of women. Men and women can experience mood disorders and the chronic abuse could result in high risk of suffering cardiovascular disease and prostate cancer <ref name="Steroids" />.
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| Because of the doping scandals in the athlete community, the World Anti-Doping Agency (WADA) has prohibited them <ref name="Steroids" />. This creates the need to discover androgens that have beneficial anabolic activity with reduced androgenic activity.
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| ==Non-Steroid==
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| ===Selective Androgen Receptor Modulators (SARMs)===
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| Steroid androgens can be associated with a high rate of adverse effects, which limits their widespread clinical use. To overcome these side effects, SARMs were developed.
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| SARMs are small molecule drugs that manipulate the AR function in different tissues <ref name="SARMs knowledge" />. They can act as both agonist and antagonist, making them potential to treat AR-related diseases.
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| These non-steroidal drugs normally can be administered orally or using a transdermal injection <ref name="NR” /><ref name="SARMs therapy” /> having better compliance and there are not affected by 5α-reductase (limiting its androgenic risk effects) and aromatase (limiting its estrogenic risk effects) <ref name="NR” /><ref name="SARMs therapy” />. Those characteristics help to the reduction of side effects related with the use of natural androgens and the tissue selectivity of these drugs make them a suitable option to treat a great group of diseases skipping the risk related with the use of TRT <ref name="NR” /><ref name="SARMs therapy” /><ref name="SARMs" />.
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| Also, some SARMs could be a suitable option to achieve the improvement in anabolic activity and muscular density obtained by the use of AAs without the unwanted side effects associated with their androgenic action of those drugs <ref name="Steroids" />.
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| ====Mechanism of SARMs====
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| Currently SARMs tissue selectivity is still under research <ref name="SARMs" /><ref name="Steroids" />. There is no consensus on SARMs mechanisms of action. However, there are two hypotheses that could explain it:
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| It could be related with their non-steroidal composition and with the fact that they are unaffected by 5α-reductase <ref name="SARMs therapy” /><ref name="SARMs" /><ref name="Steroids" /> which promotes the interaction of AR with tissue-specific coactivators.
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| The way SARMs bind to the AR is what primarily enhances or represses their effect. Each SARM-AR complex has a different conformation and tissues have unique patterns of AR expression, co-regulatory proteins levels and transcriptional regulation <ref name="SARMs knowledge" />.
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| When a ligand promotes interactions between the N- and C-terminal AR domains, the AR is maximally active. The ability to reduce N/C interactions is the hallmark of SARMs that display antagonisms in androgenic tissues <ref name="SARMs knowledge" />.
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| ====Diseases that could be treated with SARMs====
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| SARMs may one day play a role in the treatment of cognitive disorders, such as '''Alzheimer's disease'''. Androgens facilitate the reduction of deleterious ß-amyloid (ßA) plaques, upregulating the expression of ßA-degrading neprilysin and they promote synapse formation and neurogenesis, upregulating brain derived neurotrophic factor <ref name="Steroids" />.
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| AR in '''breast cancer''' likely confers survival advantage by modulating ER signaling, which may reduce the risk of metastasis and aggressive disease. There is a clinical trial seeking to evaluate pembrolizumab and enobosarm co-therapy for the treatment of AR positive metastatic triple negative breast cancer <ref name="SARMs knowledge" />.
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| '''Urinary incontinence''' denotes involuntary bladder urine leakage amongst women commonly with decreased pelvic muscle strength. As the pelvic floor muscles contain high levels of AR, it is a relevant target for SARM therapy <ref name="Steroids" />.
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| ====Side effects====
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| Despite the consistent effect demonstrated by SARMs on lean body mass accrual, reductions in high-density lipoprotein (HDL) with even low doses seem to be an important concern with these compounds, though it occurs to a lesser extent compared to testosterone <ref name="clinical trials">PMID: 32476495</ref>.
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| SARMs administration has also been related to hepatotoxicity and some compounds have shown liver enzymes alterations, the most common adverse events being increases in alanine transaminase and aspartate transaminase <ref name="clinical trials" />.
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| The anabolic effects of SARMs and their lack of androgenic side effects have made them of great interest to the bodybuilding community and create the potential for abuse among competitive athletes <ref name="SARMs knowledge" />. | |
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| ===Antagonist===
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| These kinds of drugs were developed with the objective to avoid the secondary effects associated with cross reactivity of steroidal ARA, increasing the selectivity and the affinity to the androgen receptor, limiting the association with other steroids nuclear receptors <ref name="bicalutamide" />. Also, their non-steroidal structure improved oral bioavailability being another advantage in comparison with steroidal ARA <ref name="bicalutamide" />. Some examples are flutamide, bicalutamide <ref name="ARA prostate” /><ref name="bicalutamide" /><ref name="Bicalutamide functions">PMID: 12015321</ref><ref name="Unexpected">PMID: 21506597</ref><ref name="nonsteroidal" /><ref name="Role of AR">PMID: 30209899</ref> or apalutamide (ARN-509) <ref name="ARA prostate” /><ref name="Role of AR” />.
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| ====Bicalutamide====
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| R-<scene name='85/857155/Bicatulamide_in_ar/1'>bicatulamide</scene>, marketed as Casodex <ref name="ARA prostate” /><ref name="nonsteroidal" />, is one of the most stable and tolerated androgen receptor antagonists used in the treatment of prostate cancer <ref name="ARA prostate” /><ref name="bicalutamide" /><ref name="AAWS">PMID: 28971898</ref>, belonging to the first generation of antiandrogens developed <ref name="ARA prostate” /><ref name="MoA">PMID: 35245614</ref>. It is a competitive antagonist <ref name="Bicalutamide functions” /><ref name="MoA" /><ref name="AAWS" /> which binds to the LBD producing a transcriptionally inactive androgen receptor <ref name="Bicalutamide functions” />. However, it seems that the long-term use of these drugs and other first generation antiandrogens leads to withdrawal syndrome in prostate cancer resistant to castration patients <ref name="ARA prostate” /><ref name="nonsteroidal" />. In many cases associated androgen receptor mutations like W741L that can switch the mechanism of action of the drug from antagonist to agonist or partial agonist <ref name="ARA prostate” /><ref name="bicalutamide" /><ref name="MoA" /><ref name="Unexpected” /><ref name="nonsteroidal" />.
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| Although bicalutamide has been patented since 1982 and approved to be clinical used by the FDA since 1995 <ref name="bicalutamide" />, its mechanism of action it's still a debate, because the X-ray structure of the wild-type androgen receptor binded to an antagonist is not yet solved <ref name="MoA" />.
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| Changes in the conformation of the androgen receptor due to association with antagonists have been hypothesized to be similar to those produced in the steroid receptor family <ref name="ARA prostate” /><ref name="MoA" />.
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| When an agonist or a ligand binds to the LBD it seems that it induces a conformation of the steroid receptor which makes H12 close off the pocket of LBD allowing the union of cofactors so, at the end, permitting the steroid receptor function allowing the DNA transcription <ref name="ARA prostate” />. Although, when an antagonist is binded, H12 seems to be more separated to the LBD, disabling the binding of coactivators <ref name="ARA prostate” /> and the migration of the nuclear receptor into the nucleus <ref name="MoA" />.
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| Nonetheless, the AR has some structural singularities that may not let this change of conformation, being the most important the additional C-terminal region in H12 anchored to the receptor by the formation of a ß-sheet, limiting its movement <ref name="ARA prostate” /><ref name="MoA" />. Due to this structural difference, in silico approaches have suggested that the antiandrogen effect of bicalutamide may be produced by the instability of the homodimer <ref name="MoA" />. That may lend to the homodimer dissociation preventing the transcriptional activity of the AR explaining the mechanism of action of this drug <ref name="MoA" />. Also, in silico analysis have shown that the W741L mutation leads to a bicalutamide-AR homodimer more stable, which may make some insight into the withdrawal syndrome observed in bicalutamide treatment <ref name="MoA" />.
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| It is mandatory to understand by future research the whole mechanism of action of the current antiandrogens clinically used, with the objective of developing new drugs which can escape to the antagonist-agonist switch seen by bicalutamide, or other antiandrogens like flutamide.
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| One example of this is apalutamide, a non-steroidal second generation antiandrogen <ref name="ARA prostate” /><ref name="Role of AR” /> approved for use in non metastatic castration resistant prostate cancer patients by the FDA in 2018 <ref name="Role of AR” />. See also the SPARTAN study <ref>PMID: 29420164</ref>: [https://clinicaltrials.gov/ct2/show/NCT01946204]. This new drug has promising uses but it is still associated with side effects like an increased level of falls in patients with the treatment vs placebo <ref>PMID: 36209239</ref>.
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| =References=
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| <references />
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| <StructureSection load='3b5r' size='350' side='right' caption='AR' scene=''>
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| <scene name='85/857155/H12_androgen_receptor/1'>H12</scene>
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| <scene name='85/857155/Bicatulamide_in_ar/1'>bicatulamide</scene>
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| </StructureSection>
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