XY 018

XY018 is a potent ROR-γ-selective antagonist. XY018 inhibits ROR-γ constitutive activity in 293T cells with high potency (EC50, 190 nM). XY018 binds to the ROR-γ hydrophobic ligand binding domain (LBD)[1].

Signaling Pathways >> Metabolic Enzyme/Protease >> ROR

Research Areas >> Cancer

Research Areas >> Inflammation/Immunology

ROR-γ:0.19 μM (IC50, in 293 T cells)

ROR-α:7.57 μM (IC50, in 293 T cells)

XY018 (0.07-10 μM; 4 days) inhibit CRPC tumors C4-2B cells growth and survival[1]. XY018 inhibits Gal4-RORγ-LBD and Gal4-RORα-LBD with IC50s of 0.19±0.02 and 7.57 μM in 293 T cells, respectively[2]. XY018 shows anti-proliferation effects against the prostate cancer cell lines LNCaP, 22Rv1, C4-2B, DU145, and PC-3 with IC50s of 5.14±0.36, 9.00±0.33, 9.20, 28.43±0.89, and 11.14±1.78 μM, respectively[2]. Cell Viability Assay[1] Cell Line: CRPC tumors C4-2B Concentration: 0.07, 0.15, 0.31, 0.62, 1.25, 2.5, 5, and 10 μM Incubation Time: 4 days Result: Inhibited growth and survival.

XY018 (5 mg/kg; intraperitoneally i.p.; five times per week for 23 days) inhibit CRPC tumor growth in mice[1] . XY018 (10 mg/kg orally or 2 mg/kg intravenously) exhibits reasonable pharmacokinetics profiles in SD rats[2]. Animal Model: Four-week-old male SCID C.B17 mice (for C4-2B and VCaP) or BALB/c nu/nu athymic mice (for 22Rv1 and PC-3)[1] Dosage: 5 mg/kg Administration: Treated intraperitoneally (i.p.); five times per week for 23 days Result: Tumor growth inhibition. Animal Model: Sprague Dawley rats[2] Dosage: 10 mg/kg (po; 1 mg/mL); 2 mg/kg (iv;0.4 mg/mL) (Pharmacokinetic Analysis) Administration: Orally administrated (10 mg/kg) and intravenously administrated (2 mg/kg); single dose Result: High plasma exposure AUC(0–∞) value of 6444 (μg/L·h), half-life (T1/2=7.67±2.36 h) and maximum plasma concentration (Cmax) value of 839 (μg/L) after a 2 mg/kg iv administration. Demonstrated a relatively low oral bioavailability of 19% after an oral administration.

[1]. Junjian Wang, et al. ROR-γ Drives Androgen Receptor Expression and Represents a Therapeutic Target in Castration-Resistant Prostate Cancer. Nat Med. 2016 May;22(5):488-96.

[2]. Yan Zhang, et al. Discovery and Characterization of XY101, a Potent, Selective, and Orally Bioavailable RORγ Inverse Agonist for Treatment of Castration-Resistant Prostate Cancer. J Med Chem. 2019 May 9;62(9):4716-4730.