D4-abiraterone

D4-abiraterone is a major metabolite of abiraterone. D4-abiraterone is an inhibitor of CYP17A1, 3b-hydroxysteroid dehydrogenase (3βHSD) and steroid-5a-reductase (SRD5A) and also an antagonist of androgen receptor. IC50 & Target:CYP17A1, 3βHSD, SRD5A, androgen receptor^[1] In Vitro:D4-abiraterone (10 mM) nearly completely blocks conversion from D4-androstenedione (AD) to 5α-androstanedione and other 5α-reduced androgens. The affinity of D4-abiraterone for mutant (expressed in LNCaP, half-maximum inhibitory concentration (IC₅₀=5.3 nM)) and wild type (expressed in LAPC4, IC₅₀=7.9 nM) androgen receptor (AR) is greater than that of Abiraterone (IC₅₀=418 and >500 nM, respectively). Compare with Abiraterone, D4-abiraterone clearly better suppresses PSA, TMPRSS2 and FKBP5 expression in LNCAP, LAPC4 and C4-2 cell lines. D4-abiraterone also inhibits AR target gene expression in a dose-dependent manner^[1]. In Vivo:D4-abiraterone is tenfold more potent than Abiraterone in blocking conversion from dehydroepiandrosterone (DHEA) by 3β-hydroxysteroid dehydrogenase (3βHSD) to D4-androstenedione (AD) in LNCaP and VCaP xenografts. 0.1 μM D4-abiraterone is equivalent to 1 μM Abiraterone for blocking AD accumulation at 48 h in both LNCaP and VCaP xenografts. Progression is significantly delayed in the D4-abiraterone group compare with the Abiraterone acetate group^[1].