Abstract
Galeterone is a steroidal CYP17A1 inhibitor, androgen receptor (AR) antagonist, and AR degrader, under evaluation in a phase III clinical trial for castration-resistant prostate cancer (CRPC). The A/B steroid ring (Δ5,3β-hydroxyl) structure of galeterone is identical to that of cholesterol, which makes endogenous steroids with the same structure (e.g., dehydroepiandrosterone and pregnenolone) substrates for the enzyme 3β-hydroxysteroid dehydrogenase (3βHSD). We found that galeterone is metabolized by 3βHSD to Δ4-galeterone (D4G), which is further converted by steroid-5α-reductase (SRD5A) to 3-keto-5α-galeterone (5αG), 3α-OH-5α-galeterone, and 3β-OH-5α-galeterone; in vivo it is also converted to the three corresponding 5β-reduced metabolites. D4G inhibits steroidogenesis and suppresses AR protein stability, AR target gene expression, and xenograft growth comparably with galeterone, and further conversion by SRD5A leads to loss of several activities that inhibit the androgen axis that may compromise clinical efficacy. Together, these findings define a critical metabolic class effect of steroidal drugs with a Δ5,3β-hydroxyl structure.