GSK484 (hydrochloride)

GSK484 hydrochloride is a selective and reversible peptidylarginine deiminase 4 (PAD4) inhibitor. GSK484 hydrochloride demonstrates high affinity binding to PAD4 with IC₅₀s of 50 nM in the absence of Calcium. In the presence of 2 mM Calcium, notably lower potency (250 nM) is observed. IC50 & Target:IC50: 50 nM (PAD4, in the absence of Calcium), 250 nM (PAD4, in the presence of 2 mM Calcium)^[1] In Vitro:GSK484 demonstrates high affinity binding to the low-calcium form of PAD4 with IC₅₀s of 50 nM and 250 nM in the absence of Calcium (0 mM) and Calcium (2 mM), respectively. GSK484 also inhibits PAD4 citrullination (at 0.2 mM Calcium) of benzoyl-arginine ethyl ester (BAEE) substrate in a concentration-dependent manner, as detected using an NH₃ release assay^[1]. In Vivo:To address whether PAD4 inhibition can suppress cancer-associated kidney injury, MMTV-PyMT mice are treated with the PAD4 inhibitor GSK484 at 4 mg/kg daily for one week. This dose suppress the elevated number of neutrophils undergoing NETosis in peripheral blood in mice with cancer. In parallel, the total protein level in urine from MMTV-PyMT mice is significantly reduced compared with untreated tumor-bearing mice, further supporting an improved functional status of the kidneys after GSK484 treatment. Administration of GSK484 at a dose of 4 mg/kg daily during one week reverts signs of kidney dysfunction in tumor-bearing mice to the same extent as DNase I treatment, without any detectable signs of toxicity^[2].