David Porubek Pages 1364 - 1384 ( 21 )
Cytochrome P450 17A1 (CYP17A1; also P450c17and P450sccII) is a critically important enzyme in humans that catalyzes the formation of all endogenous androgens. It is an atypical cytochrome P450 enzyme in that it catalyzes two distinct types of substrate oxidation. Through its hydroxylase activity, it catalyzes the 17α -hydroxylation of pregnenolone to 17 α-OH pregnenolone. Subsequently, through its C17,20lyase activity, it can further convert 17 α-OH pregnenolone to the androgen dehydroepiandrosterone, which is a precursor to androstenedione, testosterone, and dihydrotestosterone. The importance of androgens in diseases such as prostate cancer has been appreciated for decades and the discovery of extra-testicular formation of androgens has helped clarify the pathology of the disease, especially the castrate- resistant disease. Therefore, specific inhibition of CYP17A1 by therapeutic intervention has been an area of considerable effort in several research laboratories. This basic research has led to the discovery of several promising drug candidates followed by the conduct of several clinical trials. Recently, all these efforts have culminated in the first approval by FDA of an inhibitor of CYP17A1 for the treatment of castrate-resistant prostate cancer. Ongoing clinical trials are now evaluating the agent in earlier stages of prostate cancer and even rare forms of androgen–dependent breast cancer. Accordingly, this review focuses on the biochemistry, chemistry, and clinical inhibitors of CYP17A1.
Abiraterone, androgen, androstenedione, CYP17A1, cytochrome P-450, prostate cancer, testosterone.
Department of Medicinal Chemistry, School of Pharmacy, University of Washington, Seattle, Washington 98195.