Multiple targeted actions of CYP17 inhibitors on prostate cancer cells

Cytochrome P450 17a-hydroxylase, c17-20-lyase (CYP17) is one of the enzymes involved in androgen biosynthesis in the human body. Its inhibition has traditionally been recognized as an important strategy for PC treatment as a way to lower androgen levels and thus stop disease progression Ketoconazole, a non steroidal antifungal compound which was reported to cause gynecomastia in male patients, was the first to be used clinically for PC treatment. After ketoconazole, a series of compounds, both steroidal and non steroidal, have been synthesized and evaluated as CP17 inhibitors in the hope of finding more potent molecules with a better side effects' profile.
Pre-clinical evaluation of several compounds designed as CYP17 inhibitors has shown that some of these compounds were able to interact with other molecular targets concomitantly, such as the androgen receptor (AR) which is involved in disease progression, and might therefore bear additional interest as promiscuous agents for PC treatment. This communication will describe our efforts and results in the synthesis of two series of novel androstane derivatives, generally designated as indazole derivatives and C17 2'-methylimidazole derived carbamates. Some of these compounds were found to inhibit CYP17 and also bind to the AR, blocking AR mediated transcription. Moreover, they inhibited the proliferation of the most common PC cell line models, namely LNCaP, PC-3 and LAPC4 cells.