Bicalutamide

Bicalutamide, marketed as Casodex ^[1][2], is one of the most stable and tolerated Androgen receptor (AR) antagonists (ARA) used in the treatment of prostate cancer ^[1][3][4], belonging to the first generation of antiandrogens developed ^[1][5].

It is a competitive antagonist ^[6][5][4] which binds to the Ligand-binding Domain (LBD) producing a transcriptionally inactive AR ^[6]. 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 ^[1][2]. In many cases, associated AR mutations, like W741L, can switch the mechanism of action of the drug from antagonist to agonist or partial agonist ^{[1][3][2][7][5]}.

Androgen Receptor Ligand-binding Domain W741L Mutant Complex with R-bicalutamide (1z95).

Bicalutamide binding site.

Although bicalutamide has been patented since 1982 and approved to be clinical used by the FDA since 1995 ^[3], 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 ^[5]. 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 ^[1][5].

When an agonist or a ligand binds to the LBD, it seems to induce a conformation of the steroid receptor which makes H12 closes off the pocket of LBD allowing the binding of cofactors. That permits the steroid receptor function allowing the DNA transcription ^[1]. Although, when an antagonist is bound, H12 seems to be more separated from the LBD, disabling the binding of coactivators ^[1] and the migration of the nuclear receptor into the nucleus ^[5].

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 ^[1][5]. 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 ^[5]. 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 ^[5]. 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 ^[5].

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 ^[1][8], approved for use in non metastatic castration resistant prostate cancer patients by the FDA in 2018 ^[8]. See also the SPARTAN study^[9]. 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 ^[10].