Prostate cancer progression can be associated with androgen receptor (AR) mutations acquired following treatment with castration and/or an anti-androgen. Abiraterone, a rationally-designed inhibitor of CYP17A1 recently approved for the treatment of docetaxel-treated castration-resistant prostate cancer (CRPC), is often effective, but requires co-administration with glucocorticoids to curtail side effects. Here we hypothesized that progressive disease on abiraterone may occur secondary to glucocorticoid-induced activation of mutated AR. We found that prednisolone plasma levels in CRPC patients were sufficiently high to activate mutant AR. Mineralocorticoid receptor antagonists, such as spironoloactone and eplerenone that are used to treat side-effects related to mineralocorticoid excess, also bound to and activated signaling through both wild-type and mutant AR. Abiraterone inhibited in vitro proliferation and AR-regulated gene expression of AR-positive prostate cancer cells, which could be explained by AR antagonism in addition to inhibition of steroidogenesis. Interestingly, activation of mutant AR by eplerenone was inhibited by MDV3100, bicalutamide or greater concentrations of abiraterone. Therefore, an increase in abiraterone exposure above this threshold could reverse resistance secondary to activation of AR by residual ligands or co-administered drugs. Together, our findings provide a strong rationale for clinical evaluation of combined CYP17A1 inhibition and AR antagonism.

https://cancerres.aacrjournals.org/content/canres/72/9/2176.full.pdf

Interactions of Abiraterone, Eplerenone, and Prednisolone with Wild-type and Mutant Androgen Receptor: A Rationale for Increasing Abiraterone Exposure or Combining with MDV3100

Targeting cytochrome P450 enzymes: a new approach in anti-cancer drug development.

Synthesis, anticonvulsant, and anti-inflammatory evaluation of some new benzotriazole and benzofuran-based heterocycles.

Anticancer steroids: linking natural and semi-synthetic compounds

The androgen receptor (AR), ligand-induced transcription factor, is expressed in primary prostate cancer and in metastases. AR regulates multiple cellular events, proliferation, apoptosis, migration, invasion, and differentiation. Its expression in prostate cancer cells is regulated by steroid and peptide hormones. AR downregulation by various compounds which are contained in fruits and vegetables is considered a chemopreventive strategy for prostate cancer. There is a bidirectional interaction between the AR and micro-RNA (miRNA) in prostate cancer; androgens may upregulate or downregulate the selected miRNA, whereas the AR itself is a target of miRNA. AR mutations have been discovered in prostate cancer, and their incidence may increase with tumor progression. AR mutations and increased expression of selected coactivators contribute to the acquisition of agonistic properties of anti-androgens. Expression of some of the coactivators is enhanced during androgen ablation. AR activity is regulated by peptides such as cytokines or growth factors which reduce the concentration of androgen required for maximal stimulation of the receptor. In prostate cancer, variant ARs which exhibit constitutive activity were detected. Novel therapies which interfere with intracrine synthesis of androgens or inhibit nuclear translocation of the AR have been introduced in the clinic.

Androgen receptor signaling in prostate cancer.

New chemical entities, steroidal C-17 benzoazoles (5, 6, 9 and 10) and pyrazines (14 and 15) were rationally designed and synthesized. The key reaction for synthesis of the benzoazoles involved the nucleophilic vinylic “addition−elimination” substitution reaction of 3β-acetoxy-17-chloro-16-formylandrosta-5,16-diene (2) and benzoazole nucleophiles, while that for synthesis of pyrazines involved palladium-catalyzed cross-coupling reaction of 17-iodoandrosta-5,16-dien-3β-ol (13) with tributylstannyl diazines. Some of the compounds were shown to be potent inhibitors of human CYP17 enzyme as well as potent antagonist of both wild type and mutant androgen receptors (AR). The most potent CYP17 inhibitors were 3β-hydroxy-17-(1H-benzimidazole-1-yl)androsta-5,16-diene (5, code named VN/124-1), 3β-hydroxy-17-(51-pyrimidyl)androsta-5,16-diene (15) and 17-(1H-benzimidazole-1-yl)androsta-4,16-dien-3-one (6), with IC50 values of 300, 500 and 915 nM, respectively. Compounds 5, 6, 14 and 15 were effective at preventing bi...

Novel C-17-Heteroaryl Steroidal CYP17 Inhibitors/Antiandrogens: Synthesis, in Vitro Biological Activity, Pharmacokinetics, and Antitumor Activity in the LAPC4 Human Prostate Cancer Xenograft Model

Rena Farquhar

Papers

Novel C-17-Heteroaryl Steroidal CYP17 Inhibitors/Antiandrogens: Synthesis, in Vitro Biological Activity, Pharmacokinetics, and Antitumor Activity in the LAPC4 Human Prostate Cancer Xenograft Model