EP4 receptor antagonist 1

EP4 receptor antagonist 1 is a highly potent and selective competitive prostanoid EP4 receptor antagonist for cancer immunotherapy. EP4 receptor antagonist 1 inhibits human and mouse EP4 receptor with IC50s of 6.1 nM and 16.2 nM, respectively. IC50s >10 μM for human EP1, EP2,and EP3 receptors[1].

Research Areas >> Cancer

Signaling Pathways >> GPCR/G Protein >> Prostaglandin Receptor

Research Areas >> Inflammation/Immunology

IC50: 6.1 nM (human EP4 receptor), 16.2 nM (mouse EP4 receptor)[1]

The antagonistic effect of EP4 receptor antagonist 1 (Compounds 59) on human EP4 in calcium flux assay with an IC50 of 6.1±0.2 nM in CHO-Gα16 cells overexpressing human EP4 receptor. The antagonistic effect of EP4 receptor antagonist 1 on human EP4 in calcium flux assay with an IC50 of 16.2±1.7 nM in CHO-Gα16 cells overexpressing mouse EP4 receptor[1]. EP4 receptor antagonist 1 dose dependently inhibits PGE2-stimulated cAMP accumulation in HEK293-EP4 cells with an IC50 of 18.7±0.6 nM. EP4 receptor antagonist 1 dose-dependently inhibits the activity of the CRE reporter in HEK293 cells with an IC50 of 5.2±0.4 nM.EP4 receptor antagonist 1 dose-dependently inhibits PGE2-stimulated β-arrestin recruitment in HEK293-EP4 cells with an IC50 of 0.4±0.1 nM[1]. EP4 receptor antagonist 1 (1 nM-10 μM) reverses PGE2-induced ERK phosphorylation in a concentration-dependent manner[1]. Western Blot Analysis[1] Cell Line: CHO-EP4 cells Concentration: 1 nM, 100 nM, 10 μM Incubation Time: Pretreated for 20 min and then subjected to 30 nM PGE2 simulation for 10 min. Result: Reversed PGE2-induced ERK phosphorylation in a concentration-dependent manner.

EP4 receptor antagonist 1 (16, 50, and 150 mg/kg; orally; once daily for two weeks) causes significant inhibition of tumor growth in BALB/c female mice. No significant body weight loss is found in any mouse cohorts. EP4 receptor antagonist 1 is well tolerated in mice at the tested dosage[1]. EP4 receptor antagonist 1 (1 mg/kg; intravenously) demonstrates moderate clearance (CL=1.7 L/h/kg) in mice with a corresponding favorable half-life (t1/2) of 4.1 h. EP4 receptor antagonist 1 (5 mg/kg; orally) exhibits good bioavailability (F=48.0%) in mice with a corresponding favorable half-life (t1/2) of 4.7 h[1]. Animal Model: BALB/c female mice (6-week-old)bearing CT26 colon cancer model[1] Dosage: 16, 50, and 150 mg/kg Administration: Orally; once daily for two weeks Result: Tumor growth inhibition (TGI) was 24.6% at 16 mg/ kg, 54.7% at 50 mg/kg, and 63.8% at 150 mg/kg. Animal Model: BALB/c female mice[1] Dosage: 1 mg/kg and 5 mg/kg (Pharmacokinetic Analysis) Administration: Intravenously or orally at a dose of 1 mg/kg (5 mL/kg) and 5 mg/kg (10 mL/kg),respectively. Result: Demonstrated moderate clearance ( CL=1.7 L/h/kg) in mice with a corresponding favorable half-life (t1/2) of 4.1 h at a dose of 1 mg/kg (intravenously). Exhibited good bioavailability (F=48.0%) in mice with a corresponding favorable half-life (t1/2) of 4.7 h at a dose of 5 mg/kg (orally).

[1]. Yang JJ, et al. Discovery and Characterization of 1H-1,2,3-Triazole Derivatives as Novel Prostanoid EP4 Receptor Antagonists for Cancer Immunotherapy. J Med Chem. 2020 Jan 23;63(2):569-590.