SC428 is an androgen receptor (AR) inhibitor that targets the N-terminal domain. SC428 potently decrease the transactivation of (AR)-V7, (AR)v567es, as well as full-length ( AR ) (AR-FL) and its LBD mutants, substantially. SC428 inhibits androgen-stimulated (AR)-FL nuclear translocation, chromatin binding, and (AR) -regulated gene transcription. SC428 inhibits the proliferation of tumor cells in vitro. SC428 inhibits tumor cell growth by inducing apoptosis in mice transplanted with 22RV1.
SC428 (10 nM- 1 μM, 48 h), which inhibits AR-V7 (IC50is 0.42 μM) and ARv567es (IC50 is 1.31 μM) activity in 293T (PSA-Luc)[1].SC428 (5 μM, 5 h) reverses DHT-induced thermal stabilization of AR-FL (EC50 is 0.31 μM) in LNCaP (CETSA), inhibits ligand-induced activation of AR in a concentration-dependent manner and is an antagonist of the F887 L mutant[1].SC428 (1, 2.5 and 5 μM, 30 min) inhibits the proliferation of LNCaP (IC50is 1.39 μM), VCaP (IC50 is 1.01 μM), 22RV1 (IC50 is 1.13 μM) AR-positive cell line. The ability of anti-proliferation is weak in AR-negative cell line PC3 (IC50 is 6.49 μM)[1].SC428 (5 μM, 5 h) attenuates transcription of AR-regulated genes in LNCaP-AR cells (ChIP experiments) , blocks AR-FL chromatin binding (confocal imaging experiments) , and reduces nuclear translocation[1].SC428 (2.5, 5 μmol/L, 24 h) inhibits AR signaling in prostate cancer cells that overexpress AR-V7[1].SC428 (0.5, 1, 2.5 and 5 μM, 24 h) has inhibitory effects on both LNCaP-ARV7 and LNCaP- wt cells (Enzalutamide -resistant), inhibiting PSA and UBE2C at both protein and mRNA levels (WB and qPCR) [1].SC428 (5 μM, 5 h) disrupts AR-V7 dimer (immunoprecipitation assay) and nuclear localization (confocal imaging technique) in 22RV1 cells[1].
SC428 (60 mg/kg; intraperitoneal injection; once daily; 18 days) inhibited AR-V7 tumor growth by inducing tumor cell apoptosis in mice[1].SC428 (90 mg/kg; intraperitoneal injection; five times a week; 3 weeks) inhibited the growth of AR-V7 in mice[1].
References:
[1]. Qianhui Yi , et al. Discovery of a Small-Molecule Inhibitor Targeting the Androgen Receptor N-Terminal Domain for Castration-Resistant Prostate Cancer. 2023 May 4;22(5):570-582.