Androgen receptor: Difference between revisions

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" />.

<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" />.

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" />.

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" />.  

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" />.  

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" />.

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.  

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 [https://clinicaltrials.gov/ct2/show/NCT01946204 SPARTAN study]<ref>PMID: 29420164</ref>. 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>.