CYP17 inhibitors for prostate cancer therapy

Abstract

Prostate cancer (PC) is now the second most prevalent cause of death in men in the USA and Europe. At present, the major treatment options include surgical or medical castration. These strategies cause ablation of the production of testosterone (T), dihydrotestosterone (DHT) and related androgens by the testes. However, because these procedures do not affect adrenal, prostate and other tissues' androgen production, they are often combined with androgen receptor antagonists to block their action. Indeed, recent studies have unequivocally established that in castration-resistant prostate cancer (CRPC) many androgen-regulated genes become re-expressed and tissue androgen levels increase despite low serum levels. Clearly, inhibition of the key enzyme which catalyzes the biosynthesis of androgens from pregnane precursors, 17α-hydroxy/17,20-lyase (hereafter referred to as CYP17) could prevent androgen production from all sources. Thus, total ablation of androgen production by potent CYP17 inhibitors may provide effective treatment of prostate cancer patients. This review highlights the role of androgen biosynthesis in the progression of prostate cancer and the impact of CYP17 inhibitors, such as ketoconazole, abiraterone acetate, VN/124-1 (TOK-001) and TAK-700 in the clinic and in clinical development. Article from the special issue on Targeted Inhibitors.

Figure 1. Endocrine control of prostatic growth

The growth and development of the normal prostate requires a functioning androgen signaling pathway, which is regulated by the hypothalamic–pituitary–adrenal/gonadal axis. Androgens [testosterone (T), androstenedione (AD), dehydroepiandrosterone (DHEA)] and other steroids are synthesized in the testes or adrenal glands and released into the circulation in response to specific hormonal signals [follicle stimulating hormone (FSH), gonadotropin releasing hormone (GnRH), luteinizing hormone (LH), luteinizing hormone releasing hormone (LHRH)]. Testosterone is transported by steroid hormone binding globulin (SHBG) to the prostate, where it is predominantly converted by 5α-reductase to its more active metabolite, 5α-dihydrotestosterone (DHT). The adrenals are stimulated to produce AD and DHEA by adrenocorticotropic hormone, released by the pituitary.

Figure 2. Mechanism of androgen (DHT) action

Testosterone enters the cell and is converted to DHT by the enzyme 5α-reductase. DHT binding to the AR induces conformational changes in the ligand-binding domain and causes heat shock protein dissociation from the AR. The transformed AR undergoes dimerization, phosphorylation and translocation to the nucleus. The translocated receptor dimer binds to androgen response elements in the DNA, thereby activating transcription of AR target genes and ultimately leading to cell proliferation.

Figure 3. Pathway of Steroid Biosynthesis

Figure 4. Chemical Structures of CYP17 Inhibitors in the Clinic and Clinical Trials