AR antagonist 17 is a selective, orally active androgen receptor (AR) antagonist with limited ability to cross the blood-brain barrier (IC50 = 0.010 μM). It effectively inhibits AR dimerization and nuclear translocation, demonstrating strong efficacy in various castration-resistant prostate cancer (CRPC) cells. AR antagonist 17 shows excellent effectiveness against various resistant AR mutants. It also suppresses tumor growth without notable toxicity in LNCaP xenograft models. AR antagonist 17 is useful for research in castration-resistant prostate cancer (CRPC).

AR antagonist 17 (Compound C13) demonstrates excellent AR antagonistic activity and antiproliferative effects on AR-positive prostate cancer cell lines, including LNCaP (IC 50 = 1.02 μM), C4−2B (IC 50 = 3.86 μM), 22RV1 (IC50=8.45 μM), and VCaP (IC 50 = 5.72 μM) over 72-120 hours, while showing low toxicity on the normal cell lines 3T3 and Ges-1 (IC 50 > 20 μM). At concentrations ranging from 0.2 to 2 μM over two weeks, it completely inhibits the clonal proliferation of LNCaP cells. When applied at 0.02-2 μM for 48 hours, it dose-dependently suppresses DHT-induced transcription of prostate-specific antigen (PSA) and significantly reduces mRNA levels of the AR-regulated downstream genes FKBP5 and TMPRSS2 in LNCaP cells. Furthermore, AR antagonist 17 at 0.1-10 μM for 24 hours dose-dependently inhibits endogenous PSA protein expression without significantly affecting AR protein expression in LNCaP cells. Additionally, at 0.1-10 μM for 4 hours, it dose-dependently inhibits DHT-induced AR dimerization and completely blocks this process at 10 μM in 293T cells. At a concentration of 10 μM over 8 hours, it retains AR predominantly in the cytoplasm and effectively prevents AR nuclear translocation in LNCaP cells. This compound also exhibits superior antagonistic activity against clinically relevant AR-resistant mutations, such as ARF877L/T878A (IC 50 = 0.35 μM), ARW742C (IC 50 = 0.50 μM), and ARF877L (IC 50 = 0.070 μM) over 24 hours. Markedly, AR antagonist 17 at 2 μM for 48 hours notably suppresses the expression of eight clinically related prostate cancer (PCa) recurrence markers in LNCaP cells: KLK3 (encoding PSA), TMPRSS2, KLK2, NKX3.1, SLC45A3, PMEPA1, TARP, and TM4SF1, as well as cancer-associated processes and apoptosis regulators STK39, HERC3, and GRIN3A. Additionally, it significantly inhibits the expression of pan-cancer related biomarkers associated with DNA biosynthesis and repair, including EXO1, CYP11A1, PGC, RRM2, and FAM111B in LNCaP cells.

The compound AR antagonist 17 demonstrates reduced blood-brain barrier permeability, potentially enhancing safety and minimizing central nervous system-related side effects in SD rats at a dosage of 5 mg/kg (administered orally, 2-8 hours). Additionally, when given at 40 mg/kg orally, twice daily for 32 days, it significantly inhibits tumor growth in CB17 SCID mice without causing noticeable weight loss or other signs of toxicity throughout the treatment duration.