Androgen receptor: Difference between revisions

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<scene name='89/895670/Cv/6'>Human androgen receptor bound to testosterone</scene> ([[2ylo]]).

===Antagonist: Steroid ARA===

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" />.

The development of Steroid Androgen Receptor Antagonist (ARA) 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" />.

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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===Antagonist===

'''[[Image:Non-steroideal anti-androgens.jpeg | thumb | right | Reproduced from Helsen et al. <ref name="ARA prostate" />]]'''

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="nonsteroidal" /><ref name="Bicalutamide functions">PMID: 12015321</ref><ref name="Unexpected">PMID: 21506597</ref><ref name="Role of AR">PMID: 30209899</ref> or apalutamide (ARN-509) <ref name="ARA prostate" /><ref name="Role of AR" />.

These kinds of drugs were developed with the objective to avoid the side 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="nonsteroidal" /><ref name="Bicalutamide functions">PMID: 12015321</ref><ref name="Unexpected">PMID: 21506597</ref><ref name="Role of AR">PMID: 30209899</ref> or apalutamide (ARN-509) <ref name="ARA prostate" /><ref name="Role of AR" />.

====Bicalutamide====

<scene name='54/543362/Bicalutamide_in_ar/3'>R-Bicalutamide</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="nonsteroidal" /><ref name="Unexpected" /><ref name="MoA" />.

Androgen receptor: Difference between revisions

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@@ Line 76: / Line 76: @@
 <scene name='89/895670/Cv/6'>Human androgen receptor bound to testosterone</scene> ([[2ylo]]).
 ===Antagonist: Steroid ARA===
-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" />.
+The development of Steroid Androgen Receptor Antagonist (ARA) 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" />.
 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" />.
@@ Line 111: / Line 111: @@
 ===Antagonist===
 '''[[Image:Non-steroideal anti-androgens.jpeg | thumb | right | Reproduced from Helsen et al. <ref name="ARA prostate" />]]'''
-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="nonsteroidal" /><ref name="Bicalutamide functions">PMID: 12015321</ref><ref name="Unexpected">PMID: 21506597</ref><ref name="Role of AR">PMID: 30209899</ref> or apalutamide (ARN-509) <ref name="ARA prostate" /><ref name="Role of AR" />.
+These kinds of drugs were developed with the objective to avoid the side 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="nonsteroidal" /><ref name="Bicalutamide functions">PMID: 12015321</ref><ref name="Unexpected">PMID: 21506597</ref><ref name="Role of AR">PMID: 30209899</ref> or apalutamide (ARN-509) <ref name="ARA prostate" /><ref name="Role of AR" />.
 ====Bicalutamide====
 <scene name='54/543362/Bicalutamide_in_ar/3'>R-Bicalutamide</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="nonsteroidal" /><ref name="Unexpected" /><ref name="MoA" />.