ARN-509 (Apalutamide)

Apalutamide (ARN-509) (< 10 μM) inhibits androgen-mediated induction or repression of mRNA expression levels for 13 endogenous genes including PSA and TMPRSS2 in the LNCaP/AR prostate cancer cell line. It also inhibits the proliferative effect of R1881 (30 pM) in the same cell line. At 10 μM, this compound impairs AR nuclear localization and thus reduces the concentration of AR available to bind androgen response elements (ARE) in LNCaP cells expressing AR-EYFP. It is able to effectively compete with R1881 (1 nM) and prevent AR from binding to promoter regions. Additionally, it inhibits R1881-induced VP16-AR–mediated transcription with IC50 of 0.2 μM in Hep-G2 cells expressing a VP16-AR fusion protein and an ARE-driven luciferase reporter. [1]

Apalutamide (ARN-509) (10 mg/kg/d, oral) inhibits tumor growth with decreased proliferative index and increased apoptotic rate in castrate male immunodeficient mice harboring LNCaP/AR-luc xenograft tumors. This compound dose dependently inhibits tumor growth with highest efficacy at dose of 30 mg/kg/day in castrate male immunodeficient mice harboring LNCaP/AR-luc xenograft tumors. It dosed at 10 mg/kg/d for 28 days results in a 3-fold reduction in prostates weight associated with lacking glandular secretory activity and 1.7-fold reduction in epididymis weight in adult male dogs. The compound (10 mg/kg/d, oral) inhibits cell proliferation of prostate tissues in adult male dogs. [1] It is safe and well tolerated in 24 patients with metastatic CRPC who has progressed on prior treatments and peak plasma concentrations occurred 2 to 3 hours after administration. This agent results in durable PSA declines at doses ranging from 30 to 300 mg in patients with metastatic CRPC. [2] It shows powerful anti-cancer activity and induces durable remissions long after therapy completion in castrate resistant prostate cancer mouse models. [3]

Apalutamide (ARN-509) is added in a 16 μL volume to the RPMI culture medium after cells are incubated for 48 hours. For the antagonist mode assay, it is diluted in culture medium also containing 30 pM R1881. After 7 days' incubation, 16 μL of CellTiter-Glo Luminescent Cell Viability Assay is added and Relative Luminescence Units (RLUs) measured.

• https://pubmed.ncbi.nlm.nih.gov/22266222/
• http://www.asco.org/ASCOv2/Meetings/Abstracts?&vmview=abst_detail_view&confID=116&abstractID=89154
• http://www.pcf.org/atf/cf/%7B7C77D6A2-5859-4D60-AF47-132FD0F85892%7D/PCFStateScience2010.pdf