Molecule

Description

Abiraterone acetate (CB7630, CB 7630, CB-7630) is an acetate salt form of Abiraterone which is a steroidal cytochrome CYP17 inhibitor with IC50 of 72 nM.

Targets

IC₅₀

In Vitro

Abiraterone shows a good complexation with the heme iron only in SM1. ^[1] Abiraterone blocks the synthesis of androgens by inhibiting CYP17A1. Abiraterone also blocks 3β-hydroxysteroid dehydrogenase (3βHSD), an enzyme that is absolutely required for the synthesis of biologically active androgens. Abiraterone inhibits conversion of DHEA to Δ⁴-androstenedione. Abiraterone inhibition of 3βHSD blocks DHT synthesis and the androgen receptor response. Abiraterone inhibits the conversion of Δ⁵-androstenediol to testosterone. ^[2] Abiraterone inhibits C_17,20-lyase, with an IC50 of 5.8 nM, in rat testis microsomes. Abiraterone significantly inhibits testosterone secretion (?48%) and in turn increases LH concentration (192%). ^[3] Abiraterone inhibits in vitro proliferation and AR-regulated gene expression of AR-positive prostate cancer cells, which could be explained by AR antagonism in addition to inhibition of steroidogenesis. ^[4]

In Vivo

Treatment with Abiraterone significantly inhibits castration-resistant prostate cancer progression in the robustly growing subset, effectively putting a ceiling on tumor growth over 4 weeks of treatment. ^[3] After 3 days of oral treatment at 50 mg/kg per day, Abiraterone, markedly inhibits ventral prostate (?14%) and seminal vesicles weights (?37%) without affecting adrenal weight (?7%). ^[3]

Clinical Trials

Abiraterone has entered in a phase II clinical trial in the treatment of castration-resistant prostate cancer and stage IV prostate cancer.

Features

Abiraterone is a drug used in castration-resistant prostate cancer.

C17,20-lyase activity assay

Microsomes are diluted to a final protein concentration of 50 μg/mL in the reaction mixture which contains 0.25 M sucrose, 20 mM Tris-HCl (pH 7.4), 10 mM G6P and 1.2 IU/mL G6PDH. After equilibration at 37 °C for 10 minutes, the reaction is initiated by addition of βNADP to obtain a final concentration of 0.6 mM. Prior to the distribution of 600 μL of the reaction mixture in each tube, test compounds are evaporated to dryness under a stream of nitrogen and then are incubated at 37 °C for 10 minutes. After incubation with Abiraterone, 500 μL of the reaction mixture is transferred to tubes containing 1 μM of the enzyme substrate, 17OHP. After a further 10 minutes incubation, tubes are placed on ice and the reaction is stopped by addition of 0.1 ml NaOH 1N. Tubes are deep-frozen and stored at -20 °C until assayed for Δ4A levels. A Δ4A RIA is developed and automated on a microplate format in our laboratory using a specific antibody against Δ4A and instructions provided by Biogenesis. The separation of free and bound antigen is achieved with a dextran-coated charcoal suspension. After centrifugation, aliquots of the clear supernatant are counted in duplicates in a liquid scintillation counter. The Δ4A concentrations of unknown samples are determined from the standard curve. The detection limit is 0.5 ng/mL and the within and between assay coefficients of variation are 10.7 and 17.6%, respectively at an assay value of 13 ng/mL. The rate of enzymatic reaction is expressed as pmol of Δ4A formed per 10 minutes and per mg of protein. The value of maximum activity without inhibitor (control) is set at 100%. The IC50 values are calculated using non-linear analysis from the plot of enzyme activity (%) against log of inhibitor concentration.

Cell Lines

LNCaP and VCaP cells

Concentrations

0 μM -10 μM

Incubation Time

24 hours and 96 hours

Methods

LNCaP and VCaP cells are seeded in 96-well plates and grown in CSS-supplemented phenol red–free or FBS-supplemented media for 7 days. Cells are treated with Abiraterone at 24 hours and 96 hours after plating and cell viability is determined on day 7 by adding CellTiter Glo and measuring luminescence.

Animal Models

Male NOD/SCID mice with LAPC4 cells

Formulation

0.1 mL 5% benzyl alcohol and 95% safflower oil solution

Doses

0.5 mmol/kg/d

Administration

Administered via s.c.