Unfortunately, the recurrence of androgen-insensitive or ‘castration-resistant prostate cancer (CRPC)’ is often observed in patients. Current treatments for CRPC employ radiopharmaceutical, immunotherapeutic and chemotherapeutic approaches. Among the frontline chemotherapeutic agents for CRPC is a steroidal antiandrogen marketed under the trade name Zytiga. Zytiga (abiraterone) is an androgen synthesis inhibitor that is used in combination with another steroid, prednisone. The anticancer drug inhibits cytochrome P450 subtype 17A1 (CYP17A1), an enzyme with both 17a-hydroxylase and 17,20-lyase activities, which plays a critical role in the steroidogenic pathway that produces endogenous androgen hormones. Biosynthetically, CYP17A1 catalyzes the C17a-hydroxylation of pregnenolone and progesterone (see Figure above) and also acts upon those hydroxylated metabolites to excise the side-chain from the steroid nucleus (the lyase activity), furnishing the intact androgen receptor ligands. Inhibition of CYP17A1 by Zytiga effectively decreases circulating levels of androgens such as DHEA, testosterone and dihydrotestosterone. Zytiga also acts as an antagonist of the androgen receptor and as an inhibitor of the enzyme 3b-hydroxysteroid dehydrogenase (3b-HSD), further reinforcing its efficacy as an antiandrogenic treatment for metastatic CRPC. Zytiga therapy generally prolongs survival by 4.6 months when compared to placebo but durable responses are not always observed, presumably due to acquired resistance. Therefore, new therapeutic intervention strategies for resistant PC with an androgen-depletion-independent phenotype are sought.
|Adapted from: R. M. Kris, A. A. L. Gunatilaka and co-workers. J. Med. Chem. 2015, 58, 6984.|