Steroidogenic Metabolism of Galeterone Reveals a Diversity of Biochemical Activities

Abstract

SUMMARY Galeterone is a steroidal CYP17A1 inhibitor, androgen receptor (AR) antagonist and AR degrader, and was 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 cholesterol, which makes endogenous steroids with the same structure (e.g., DHEA 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, 3β-OH-5α-galeterone, and in vivo is also converted to the 3 corresponding 5β-reduced metabolites. D4G inhibits steroidogenesis, suppresses AR protein stability, AR target gene expression and xenograft growth comparably to 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.

HSD3B1(1245A>C) variant regulates dueling abiraterone metabolite effects in prostate cancer

“…We next conducted a study in patients with metastatic CRPC who were receiving AA plus prednisone as standard-of-care treatment in order to determine if inheritance of the HSD3B1 genotype is associated with production of steroidal abiraterone metabolites that are regulated by the cognate 3βHSD1 enzyme ( Table 1). In the context of low versus high 3βHSD1 enzymatic activity, robust 5α-reductase activity (which follows 3βHSD) would be expected to lead to low versus high levels of 5α-reduced steroid metabolites (22). We therefore hypothesized that inheritance of the HSD3B1(1245C) variant that encodes for a protein degradation-resistant enzyme would correlate with higher serum concentrations of 5α-abiraterone metabolites, including 3-keto-5α-Abi, which exhibits AR agonist activity (19).…”

Formation and Cleavage of C–C Bonds by Enzymatic Oxidation–Reduction Reactions

“…The answer is relevant not only to issues with individuals devoid of lyase activity 192,248,258,260,261 but also an important consideration in any development of reaction-selective inhibitors for treatment of prostate cancer. 198,205,262–264…”

Human cytochrome P450 enzymes 5–51 as targets of drugs and natural and environmental compounds: mechanisms, induction, and inhibition – toxic effects and benefits

“…The situation is even more complex. Abiraterone is also an antagonist of the androgen receptor, and metabolites of P450 17A1 inhibitors can have their own biological activities (Alyamani et al 2017). The resulting steroid imbalances in patients treated with abiraterone can frequently lead to hypertension, hypokalemia, and adrenocortical insufficiency, which must then be monitored and treated (Pia et al 2013).…”