Abiraterone Acetate

Names

[ Name ]:
Abiraterone Acetate

[Synonym ]:
17-(3-pyridyl)-5,16-androstadien-3beta-acetate
Abiraterone acetate
Androsta-5,16-dien-3-ol, 17-(3-pyridinyl)-, acetate (ester), (3β)-
Zytiga
(3β)-17-(3-Pyridinyl)androsta-5,16-dien-3-yl acetate
(3β)-17-(pyridin-3-yl)androsta-5,16-dien-3-yl acetate
Abiraterone (acetate)

Biological Activity

[Description]:

Abiraterone acetate is an oral, potent, selective, and irreversible inhibitor of CYP17.

[Related Catalog]:

Signaling Pathways >> Metabolic Enzyme/Protease >> Cytochrome P450

Research Areas >> Cancer

[Target]

CYP17[1]

[In Vitro]

Abiraterone (Abi) acetate is an ester prodrug of the anticancer agent Abiraterone, which shows IC50 values of 15 nM and 2.5 nM for the 17,20-lyase and 17α-hydroxylase (CYP17 is a bifunctional enzyme with both 17α-hydroxylase and 17,20-lyase activity). Abiraterone inhibits human 17,20-lyase and 17α-hydroxylase with IC50 of 27 and 30 nM respectively[1]. Significant inhibition of proliferation of the AR-positive prostate cancer cell lines LNCaP and VCaP with doses of Abiraterone ≥5 μM is confirmed[2]. Abiraterone inhibits recombinant human 3βHSD1 and 3βHSD2 activity with competitive Ki values of 2.1 and 8.8 μM. 10 μM Abiraterone is sufficient to completely block synthesis of 5α-dione and DHT in both cell lines.Treatment with Abiraterone significantly inhibited CRPC progression in the robustly growing subset, effectively putting a ceiling on tumor growth over 4 weeks of treatment (P<0.00001)[3].

[In Vivo]

Abiraterone (Abi) acetate prolongs survival in castration-resistant prostate cancer (CRPC). [3H]-dehydroepiandrosterone (DHEA) depletion and Δ4-androstenedione (AD) accumulation are inhibited by Abiraterone in LNCaP, with an IC50<1 μM. The 0.5 mmol/kg/d Abiraterone treatment dose is previously shown to yield serum concentrations of about 0.5 to 1 μM. Xenograft tumor growth in the control group is widely variable, with some tumors growing slowly and only a subset of tumors exhibiting robust growth[3].

[Cell Assay]

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 (5 μM and 10 μM) at 24 and 96 hours after plating and cell viability is determined on day 7 by adding CellTiter Glo and measuring luminescence[2].

[Animal admin]

Mice[3] Male NOD/SCID mice 6 to 8 weeks of age are surgically orchiectomized and implanted with a 5 mg 90-day sustained release DHEA pellet to mimic CRPC with human adrenal physiology. Two days later, 7×106 LAPC4 cells are injected subcutaneously with Matrigel. Tumor dimensions are measured 2 to 3 times per week, and volume is calculated as length×width×height×0.52. Once tumors reach 300 mm3, mice are randomly assigned to vehicle or Abiraterone treatment groups. Mice in the Abiraterone group are treated with 5 mL/kg intraperitoneal injections of 0.5 mmol/kg/d (0.1 mL 5% benzyl alcohol and 95% safflower oil solution) and control mice with vehicle only, once daily for 5 days per week over a duration of 4 weeks (n=8 mice per treatment). Statistical significance between Abiraterone and vehicle treatment groups is assessed by ANOVA based on a mixed-effect model.

[References]

[1]. Stein MN, et al. Androgen synthesis inhibitors in the treatment of castration-resistant prostate cancer. Asian J Androl. 2014 May-Jun;16(3):387-400.

[2]. Richards J, et al. Interactions of abiraterone, eplerenone, and prednisolone with wild-type and mutant androgen receptor: a rationale for increasing abiraterone exposure or combining with MDV3100. Cancer Res. 2012 May 1;72(9):2176-82.

[3]. Li R, et al. Abiraterone inhibits 3β-hydroxysteroid dehydrogenase: a rationale for increasing drug exposure in castration-resistant prostate cancer. Clin Cancer Res. 2012 Jul 1;18(13):3571-9.

[4]. Lee GT, et al. Intracrine androgen biosynthesis in renal cell carcinoma. Br J Cancer. 2017 Mar 28;116(7):937-943.

[Related Small Molecules]

Chemical & Physical Properties

[ Density]:
1.1±0.1 g/cm3

[ Boiling Point ]:
506.7±50.0 °C at 760 mmHg

[ Melting Point ]:
127-130°C

[ Molecular Formula ]:
C₂₆H₃₃NO₂

[ Molecular Weight ]:
391.546

[ Flash Point ]:
260.2±30.1 °C

[ Exact Mass ]:
391.251129

[ PSA ]:
39.19000

[ LogP ]:
6.55

[ Vapour Pressure ]:
0.0±1.3 mmHg at 25°C

[ Index of Refraction ]:
1.584

[ Storage condition ]:
-20°C Freezer

Safety Information

[ Symbol ]:

GHS08

[ Signal Word ]:
Danger

[ Hazard Statements ]:
H360-H372

[ Precautionary Statements ]:
P201-P260-P280-P308 + P313

[ Target Organs ]:
Endocrine system

[ Hazard Codes ]:
Xi

[ RIDADR ]:
NONH for all modes of transport

[ RTECS ]:
BV7992100

[ HS Code ]:
2933399090

Precursor & DownStream

Precursor

DownStream

Customs

[ HS Code ]: 2933399090

[ Summary ]:
2933399090. other compounds containing an unfused pyridine ring (whether or not hydrogenated) in the structure. VAT:17.0%. Tax rebate rate:13.0%. . MFN tariff:6.5%. General tariff:20.0%

Articles

Phase I clinical trial of the CYP17 inhibitor abiraterone acetate demonstrating clinical activity in patients with castration-resistant prostate cancer who received prior ketoconazole therapy.

J. Clin. Oncol. 28(9) , 1481-8, (2010)

Abiraterone acetate is a prodrug of abiraterone, a selective inhibitor of CYP17, the enzyme catalyst for two essential steps in androgen biosynthesis. In castration-resistant prostate cancers (CRPCs),...

Significant and sustained antitumor activity in post-docetaxel, castration-resistant prostate cancer with the CYP17 inhibitor abiraterone acetate.

J. Clin. Oncol. 28(9) , 1489-95, (2010)

The principal objective of this trial was to evaluate the antitumor activity of abiraterone acetate, an oral, specific, irreversible inhibitor of CYP17 in docetaxel-treated patients with castration-re...

Phase II multicenter study of abiraterone acetate plus prednisone therapy in patients with docetaxel-treated castration-resistant prostate cancer.

J. Clin. Oncol. 28(9) , 1496-501, (2010)

Persistence of ligand-mediated androgen receptor signaling has been documented in castration-resistant prostate cancers (CRPCs). Abiraterone acetate (AA) is a potent and selective inhibitor of CYP17, ...