Abiraterone acetate

Abiraterone acetate, sold under the brand name Zytiga among others, is a medication used to treat prostate cancer.^[1] Specifically it is used together with a corticosteroid for metastatic castration-resistant prostate cancer (mCRPC) and metastatic high-risk castration-sensitive prostate cancer (mCSPC).^[2][3] See also Abiraterone acetate.

Abiraterone, the active metabolite of abiraterone acetate, inhibits Cytochrome P450 17A1 (CYP17A1), which manifests as two enzymes, 17α-hydroxylase (IC₅₀ = 2.5 nM) and 17,20-lyase (IC₅₀ = 15 nM) (approximately 6-fold more selective for inhibition of 17α-hydroxylase over 17,20-lyase)^[4][5] that are expressed in testicular, adrenal, and prostatic tumor tissues. See also Cytochrome P450.

Human steroidogenic cytochrome P450 17A1 mutant N52Y with inhibitor abiraterone (6wr1).

Abiraterone binding site. Water molecules are shown as red spheres.

CYP17A1 catalyzes two sequential reactions: (a) the conversion of pregnenolone and progesterone (see also progesterone) to their 17α-hydroxy derivatives by its 17α-hydroxylase activity, and (b) the subsequent formation of dehydroepiandrosterone (DHEA) and androstenedione, respectively, by its 17,20-lyase activity.^[6] DHEA and androstenedione are androgens and precursors of testosterone. Inhibition of CYP17A1 activity by abiraterone acetate thus decreases circulating levels of androgens such as DHEA, testosterone, and dihydrotestosterone (DHT). Abiraterone acetate, via abiraterone, has the capacity to lower circulating testosterone levels to less than 1 ng/dL (i.e., undetectable) when added to castration.^[4][7]