Bicalutamide: Difference between revisions
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<StructureSection load=' | <StructureSection load='' size='340' side='right' caption='Caption for this structure' scene='10/1022391/Cv/2'> | ||
Bicalutamide, marketed as Casodex <ref name="ARA prostate">PMID: 24639562</ref><ref name="nonsteroidal">PMID: 16841196</ref>, is one of the most stable and tolerated Androgen receptor (AR) antagonists (ARA) used in the treatment of prostate cancer <ref name="ARA prostate" /><ref name="bicalutamide">PMID: 15833816</ref><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 AR <ref name="Bicalutamide functions" />. However, it seems that the long-term use of these drugs and other first generation antiandrogens lead to withdrawal syndrome in prostate cancer resistant to castration patients <ref name="ARA prostate" /><ref name="nonsteroidal" />. In many cases, associated AR mutations, like W741L, 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" />. | It is a competitive antagonist <ref name="Bicalutamide functions">PMID: 12015321</ref><ref name="MoA" /><ref name="AAWS" /> which binds to the Ligand-binding Domain (LBD) producing a transcriptionally inactive AR <ref name="Bicalutamide functions" />. However, it seems that the long-term use of these drugs and other first generation antiandrogens lead to withdrawal syndrome in prostate cancer resistant to castration patients <ref name="ARA prostate" /><ref name="nonsteroidal" />. In many cases, associated AR mutations, like W741L, 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">PMID: 21506597</ref><ref name="MoA">PMID: 35245614</ref>. | ||
<scene name='10/1022391/Cv/4'>Androgen Receptor Ligand-binding Domain W741L Mutant Complex with R-bicalutamide</scene> ([[1z95]]). | |||
<scene name='10/1022391/Cv/6'>Bicalutamide binding site</scene>. | |||
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 is still under debate. The X-ray structure of the wild-type AR bound to an antagonist is not yet solved <ref name="MoA" />. Changes in the conformation of the 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" />. | 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 is still under debate. The X-ray structure of the wild-type AR bound to an antagonist is not yet solved <ref name="MoA" />. Changes in the conformation of the 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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Nonetheless, the AR has some structural singularities that may not let this change of conformation. One of the most important changes is 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 dissociation of the homodimer preventing the transcriptional activity of the AR and explaining the mechanism of action of this drug <ref name="MoA" />. In addition,'' in silico'' analysis have shown that the W741L mutation leads to a more stable bicalutamide-AR homodimer, which may provide some insight into the withdrawal syndrome observed in bicalutamide treatment <ref name="MoA" />. | Nonetheless, the AR has some structural singularities that may not let this change of conformation. One of the most important changes is 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 dissociation of the homodimer preventing the transcriptional activity of the AR and explaining the mechanism of action of this drug <ref name="MoA" />. In addition,'' in silico'' analysis have shown that the W741L mutation leads to a more stable bicalutamide-AR homodimer, which may provide some insight into the withdrawal syndrome observed in bicalutamide treatment <ref name="MoA" />. | ||
For future research, it will be useful to understand the precise mechanism of action of antiandrogens currently used in the clinic, with the objective of developing new drugs which can escape from the antagonist-agonist switch seen in bicalutamide or 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>. | For future research, it will be useful to understand the precise mechanism of action of antiandrogens currently used in the clinic, with the objective of developing new drugs which can escape from the antagonist-agonist switch seen in bicalutamide or flutamide. One example of this is apalutamide, a non-steroidal second generation antiandrogen <ref name="ARA prostate" /><ref name="Role of AR">PMID: 30209899</ref>, 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>. | ||
</StructureSection> | </StructureSection> | ||
== References == | == References == | ||
<references/> | <references/> | ||
