protein arginine deiminase

GSK484 hydrochloride (GTPL8577) is a reversible peptidyl-arginine deiminase 4 (PAD4) inhibitor. It binds to PAD4 with high affinity, with IC50 of 250 and 50 nM in the presence and absence of 2 mM calcium, respectively. GSK484 promotes the radiosensitivity of colorectal cancer (CRC) and inhibits NET formation in vitro and in vivo.

Acefylline (Theophylline-7-acetic acid), a stimulant drug of the xanthine chemical class, acts as an adenosine receptor antagonist. It is combined with diphenhydramine in the pharmaceutical preparation Etanautine to help offset its stimulant effects

Cl-amidine hydrochloride is an orally available PAD inhibitor that blocks histone 3 deimination and neutrophil extracellular trap formation and improves survival in septic mice. It induces apoptosis in cancer cells and induces miR-16 to cause cell cycle arrest.

GSK199 is a selective PAD4 inhibitor(IC50 of 200 nM in the absence of calcium).

Photoswitchable PAD inhibitor is a photoactivated protein arginine deiminase (PAD) inhibitor and a derivative of BB-Cl-amidine that contains an azobenzene photoswitch allowing optical control of PAD activity.1 Without photoactivation, it is a weak inhibitor of PAD2 (IC50 = >100 μM) and is less potent than BB-Cl-amidine in inhibiting citrulline production in vitro (kinact/KIs = 2,300, 600, 1,000, and 10,510 M-1min-1 for PAD1-4, respectively) and does not inhibit histone H3 citrullination in HEK293T cells overexpressing PAD2 when used at concentrations up to 100 μM. However, it can rapidly be photoactivated with UV-A radiation to the more active cis-isomer, which is an irreversible, competitive inhibitor of histone H3 citrullination with an IC50 value of 9.1 μM.References1. Mondal, S., Parelkar, S.S., Nagar, M., et al. Photochemical control of protein arginine deiminase (PAD) activity. ACS Chem. Biol. 13(4), 1057-1065 (2018). Photoswitchable PAD inhibitor is a photoactivated protein arginine deiminase (PAD) inhibitor and a derivative of BB-Cl-amidine that contains an azobenzene photoswitch allowing optical control of PAD activity.1 Without photoactivation, it is a weak inhibitor of PAD2 (IC50 = >100 μM) and is less potent than BB-Cl-amidine in inhibiting citrulline production in vitro (kinact/KIs = 2,300, 600, 1,000, and 10,510 M-1min-1 for PAD1-4, respectively) and does not inhibit histone H3 citrullination in HEK293T cells overexpressing PAD2 when used at concentrations up to 100 μM. However, it can rapidly be photoactivated with UV-A radiation to the more active cis-isomer, which is an irreversible, competitive inhibitor of histone H3 citrullination with an IC50 value of 9.1 μM. References1. Mondal, S., Parelkar, S.S., Nagar, M., et al. Photochemical control of protein arginine deiminase (PAD) activity. ACS Chem. Biol. 13(4), 1057-1065 (2018).

BMS-P5 free base is a specific and orally active peptidylarginine deiminase 4 (PAD4) inhibitor that blocks the formation of Neutrophil Extracellular Traps and delays the progression of multiple myeloma. Administration of BMS-P5 to multiple myeloma-bearing mice delays symptom onset and disease progression. Targeting PAD4 may be beneficial for treating multiple myeloma.

BMS-P5 is a specific and orally active Peptidylarginine Deiminase 4 (PAD4) inhibitor.

PAD2-IN-1, a benzimidazole-based derivative, is an efficacious and specific inhibitor of protein arginine deiminase 2 (PAD2). Demonstrating remarkable selectivity, PAD2-IN-1 exhibits a 95-fold higher affinity for PAD2 in comparison to PAD4 and a 79-fold higher affinity than PAD3.

GSK121 is an inhibitor of selective PAD4.

YW3-56 is an inhibitor of protein arginine deiminase 2 (PAD2) and PAD4 (IC50s = 0.5-1 and 1-5 μM, respectively).1It inhibits the growth of U2OS osteosarcoma cells (IC50= ~2.5 μM) in a p53-dependent mannerviainduction of SESN2 and subsequent inhibition of mTORC1. YW3-56 (10 mg kg) reduces tumor growth in an S-180 murine sarcoma tumor model. It also inhibits tumor growth in the 1883 MDA-MB-231 breast cancer bone metastasis mouse xenograft model.2 1.Wang, Y., Li, P., Wang, S., et al.Anticancer peptidylarginine deiminase (PAD) inhibitors regulate the autophagy flux and the mammalian target of rapamycin complex 1 activityThe Journal of Biological Chemisty287(31)25941-25952(2012) 2.Wang, S., Chen, X.A., Hu, J., et al.ATF4 gene network mediates cellular response to the anticancer PAD inhibitor YW3-56 in triple-negative breast cancer cellsMol. Cancer Ther.14(4)877-888(2015)

PAD2-IN-1 hydrochloride is a potent and selective protein arginine deiminase 2 (PAD2) inhibitor with superior selectivity for PAD2 over PAD4 (95-fold) and PAD3 (79-fold), and is a benzimidazole-based derivative.

CAY10727 is an inhibitor of protein arginine deiminase 3 (PAD3; kinact/KI= 15,600 M-1min-1).1It is selective for PAD3 over PAD1, -2, and -4 (kinact/KIs = 360, 1,110, and 1,460 M-1min-1, respectively). 1.Jamali, H., Khan, H.A., Stringer, J.R., et al.Identification of multiple structurally distinct, nonpeptidic small molecule inhibitors of protein arginine deiminase 3 using a substrate-based fragment methodJ. Am. Chem. Soc.137(10)3616-3621(2015)

PAD2-IN-2 (cis-isomer of 1) TFA is an inhibitor of protein arginine deiminase 2 (PAD2). This molecule features an azobenzene photoswitch, enabling the optical regulation of PAD activity. Additionally, PAD2-IN-2 TFA inhibits the citrullination of histone H3.

BB-Cl-Yne is a cell-permeable derivative of the protein arginine deiminase (PAD) inhibitor BB-Cl-amidine that contains an alkyne moiety for use in click chemistry reactions. BB-CL-Yne inhibits PAD1-4 with Kinact/KI values of 6,400, 3,600, 10,800, and 4,900 M-1min-1, respectively. It has been used for labeling PADs in cell-free and cell-based assays, followed by click reactions with azide-modified TAMRA or biotin reporters.

AFM-30a hydrochloride is a potent and highly selective inhibitor of protein arginine deiminase 2 (PAD2). AFM-30a hydrochloride binds to PAD2 (EC50: 9.5 μM) and inhibits H3 guanylation (EC50: 0.4 μM). AFM-30a hydrochloride can be used to study certain cancers and autoimmune diseases such as rheumatoid arthritis (RA), multiple sclerosis, lupus, and ulcerative colitis.