Abiraterone acetate: oral androgen biosynthesis inhibitor for treatment of castration-resistant prostate cancer

Abstract

Prostate cancer is the second leading cause of cancer death in men in the US and Europe. The treatment of advanced-stage prostate cancer has been androgen deprivation. Medical castration leads to decreased production of testosterone and dihydrotestosterone by the testes, but adrenal glands and even prostate cancer tissue continue to produce androgens, which eventually leads to continued prostate cancer growth despite castrate level of androgens. This stage is known as castrate-resistant prostate cancer (CRPC), which continues to be a challenge to treat. Addition of androgen antagonists to hormonal deprivation has been successful in lowering the prostate-specific antigen levels further, but has not actually translated into life-prolonging options. The results of several contemporary studies have continued to demonstrate activation of the androgen receptor as being the key factor in the continued growth of prostate cancer. Blockade of androgen production by nongonadal sources has led to clinical benefit in this setting. One such agent is abiraterone acetate, which significantly reduces androgen production by blocking the enzyme, cytochrome P450 17 alpha-hydroxylase (CYP17). This has provided physicians with another treatment option for patients with CRPC. The landscape for prostate cancer treatment has changed with the approval of cabazitaxel, sipuleucel-T and abiraterone. Here we provide an overview of abiraterone acetate, its mechanism of action, and its potential place for therapy in CRPC.

Differential molecular mechanism of docetaxel–octreotide combined treatment according to the docetaxel-resistance status in PC3 prostate cancer cells

“…Taxanes [5] and, more recently, sipuleucel-T, cabazitaxel, denosumab and abiraterone acetate [6,7], are the most active agents used in the treatment of hormone-refractory metastatic prostate cancer. In addition to its cytostatic activity, docetaxel also regulates cell signalling and the expression of certain genes [8,9].…”

Abiraterone Acetate (Zytiga®): An Inhibitor of CYP17 as a Therapeutic for Castration‐Resistant Prostate Cancer

“…Based on these observations and modelling efforts, the ICR group designed a series of steroidal structure-based analogues, bearing a pyridyl substituent at C-17, where, in the binding pocket, optimal proximity to the heme group of the P450 enzyme was predicted [16]. Thus, a first set of pregnenolone analogues (11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24) was prepared varying the position of the pyridyl nitrogen (Table 6.1). The 4-pyridyl analogues (14) were poor inhibitors of CYP17 enzymes, whereas the 2-pyridyl (13) and 3-pyridyl (11) analogues were excellent inhibitors, the latter achieving single digit nanomolar (nM) IC 50 s (Table 6.1).…”

“…Since these analogues (16)(17) were derived from native substrates of the aromatase (16), testosterone 5α-reductase (16) or estrogen receptors (17), not surprisingly, activity was retained at those enzymes and receptors (Table 6.1). On the other hand, pregnenolone-based analogues (11,13,14) showed enhanced selectivity for CYP17 over those enzymes and receptors (Table 6.2).…”

“…In conclusion, abiraterone (11), the parent form of the acetate prodrug (8), is a potent and irreversible inhibitor of human testicular 17α-hydroxylase and C 17,20 -lyase (CYP17) that has shown excellent selectivity versus aromatase and testosterone 5α-reductase.…”

“…However, severe toxic effects and the inconvenience of a thrice daily dosing schedule limited the use of ketoconazole [9]. These results sparked the search for novel inhibitors of CYP17 in the treatment of CRPC, leading to the discovery of abiraterone acetate ( Potter, at the Institute of Cancer Research in London (ICR) ( Figure 6.2) [10,11].…”