Inhibitors, Agonists, Screening Libraries www.MedChemExpress.com Immunology/Inflammation The immune system has evolved to survey and respond appropriately to the universe of foreign pathogens, deploying an intricate repertoire of mechanisms that keep responses to host tissues in check. The immune system is typically divided into two categories--innate and adaptive. Innate immunity refers to nonspecific defense mechanisms that come into play immediately or within hours of an antigen's appearance in the body. Adaptive immunity refers to antigen-specific immune response. The antigen first must be processed and recognized, and then the adaptive immune system creates an army of immune cells specifically designed to attack that antigen. For the adaptive immune system, specificity and sensitivity are provided by a large repertoire of antigen T-cell receptors (TCRs) constructed in their extracellular domain to recognize antigenic peptide fragments restricted and presented by histocompatibility complex molecules, and coupled through intracellular domains to signal transduction modules that serve to transmit environmental cues inside the cell. Inflammation is triggered when innate immune cells detect infection or tissue injury. Pattern recognition receptors (PRRs) respond to pathogen-associated molecular patterns (PAMPs) or host-derived damage-associated molecular patterns (DAMPs) by triggering activation of NF-κB, AP1, CREB, c/EBP, and IRF transcription factors. Induction of genes encoding enzymes, chemokines, cytokines, adhesion molecules, and regulators of the extracellular matrix promotes the recruitment and activation of leukocytes. Besides resolving infection and injury, chronic inflammation is a risk factor for cancer. Immunity has a major impact on inflammatory diseases and cancer, and biologics targeting immune cells and their factors. Immunosuppressant drugs suppress, or reduce, the strength of the body’s immune system, and have been used in the treatment of organ transplantation or autoimmunine diseases. Immunomodulator drugs have contributed to the significant improvement against cancer and other related diseases. References: [1] Sakaguchi S, et al. Immunol Cell Biol. 2012 Mar;90(3):277-87. doi: 10.1038/icb.2012.4. [2] Newton K, et al. Cold Spring Harb Perspect Biol. 2012 Mar; 4(3): a006049. [3] Bartneck M. Macromol Biosci. 2017 Apr 6. doi: 10.1002/mabi.201700021. www.MedChemExpress.com 1 2 Tel: 609-228-6898 Fax: 609-228-5909 Email: [email protected] Inhibitors, Agonists, Screening Libraries www.MedChemExpress.com Target List in Immunology/Inflammation • Arginase 4 • Salt-inducible Kinase (SIK) 122 • Aryl Hydrocarbon Receptor 6 • SphK 124 • CCR 11 • STING 127 • CD73 12 • Thrombopoietin Receptor 132 • Complement System 14 • Toll-like Receptor (TLR) 134 • COX 19 • CXCR 42 • Cyclic GMP-AMP Synthase 43 • FKBP 45 • FLAP 49 • Galectin 52 • Histamine Receptor 54 • IFNAR 55 • Interleukin Related 58 • IRAK 68 • MyD88 72 • NO Synthase 74 • NOD-like Receptor (NLR) 84 • PD-1/PD-L1 88 • PGE synthase 93 • Pyroptosis 97 • Reactive Oxygen Species 99 www.MedChemExpress.com 3 Arginase Arginase, an enzyme within the urea cycle in the liver, is also found in many other cells and tissues, including the lung. Arginase is present in 2 isoforms: arginase I, the hepatic isoform; and arginase II, the extrahepatic isoform; each of which is encoded by a distinct gene. The expression and function of arginase I in macrophages, hepatocytes, and vascular smooth muscle cells, is stimulated by lipopolysaccharide (LPS), IL-13, altered oxygen tension, and balloon dilatation of coronary arteries. The activation and expression of endothelial arginase II can also be induced by a variety of vascular insults. Arginase competitively inhibits nitric oxide synthase (NOS) via use of the common substrate L-arginine. Inhibition of arginase activity enhances a variety of parameters relevant to allergic airways disease, possibly by altering NO homeostasis. Arginase inhibition actively augments NO production and has beneficial effects on normal cardiac function and on vascular dysfunction typical of atherogenesis, aging, and erectile dysfunction, and sickle cell disease. 4 Tel: 609-228-6898 Fax: 609-228-5909 Email: [email protected] Arginase Inhibitors 2-Aminoimidazole Arginase inhibitor 1 Cat. No.: HY-W062216 Cat. No.: HY-15775 2-Aminoimidazole is a potent antibiofilm agent Arginase inhibitor 1 is a potent inhibitor of that can be used as an adjuvant to antimicrobial. human arginases I and II with IC50s of 223 and 509 2-aminoimidazoles disrupts the ability of bacteria nM, respectively. to protect themselves by inhibiting biofilm formation and genetically-encoded antibiotic resistance traits. Purity: >98% Purity: 98.0% Clinical Data: No Development Reported Clinical Data: No Development Reported Size: 10 mM × 1 mL, 250 mg Size: 10 mM × 1 mL, 5 mg, 10 mg, 50 mg, 100 mg BEC hydrochloride CB-1158 Cat. No.: HY-19548A (INCB01158) Cat. No.: HY-101979 BEC hydrochloride is a slow-binding and CB-1158 (INCB01158) is a potent and orally active competitive Arginase II inhibitor with Ki of 0.31 μM inhibitor of arginase, with IC50s of 86 nM and 296 and 30 nM at pH 7.5 and pH 9.5, respectively. nM for recombinant human arginase 1 and recombinant human arginase 2, respectively. Immuno-oncology agent. Purity: ≥98.0% Purity: >98% Clinical Data: No Development Reported Clinical Data: No Development Reported Size: 10 mM × 1 mL, 5 mg, 10 mg, 25 mg, 50 mg Size: 1 mg, 5 mg CB-1158 dihydrochloride DL-Norvaline (INCB01158 dihydrochloride) Cat. No.: HY-101979A (2-Aminopentanoic acid) Cat. No.: HY-W010510 CB-1158 dihydrochloride (INCB01158 DL-Norvaline, a derivative of L-norvaline, dihydrochloride) is a potent and orally active L-norvaline is a non-competitive inhibitor of inhibitor of arginase, with IC50s of 86 nM and 296 arginase. nM for recombinant human arginase 1 and recombinant human arginase 2, respectively. Immuno-oncology agent. Purity: ≥98.0% Purity: ≥97.0% Clinical Data: No Development Reported Clinical Data: No Development Reported Size: 10 mM × 1 mL, 5 mg, 10 mg, 25 mg, 50 mg, 100 mg Size: 10 mM × 1 mL, 500 mg, 5 g NED-3238 nor-NOHA acetate Cat. No.: HY-126332 (Nω-Hydroxy-nor-L-arginine acetate) Cat. No.: HY-112885A NED-3238 is a highly potent arginase I and II nor-NOHA acetate (Nω-Hydroxy-nor-L-arginine inhibitor with IC50 values of 1.3 nM and 8.1 nM, acetate) is a specific and reversible arginase respectively. inhibitor, induces apoptosis in ARG2-expressing cells under hypoxia but not normoxia. Anti-leukemic activity, effective in endothelial dysfunction, immunosuppression and metabolism. Purity: >98% Purity: ≥98.0% Clinical Data: No Development Reported Clinical Data: No Development Reported Size: 1 mg, 5 mg Size: 10 mM × 1 mL, 5 mg, 10 mg nor-NOHA monoacetate Piceatannol 3'-O-glucoside (Nω-Hydroxy-nor-L-arginine monoacetate) Cat. No.: HY-112885B (Quzhaqigan) Cat. No.: HY-N2237 nor-NOHA (Nω-Hydroxy-nor-L-arginine) monoacetate Piceatannol 3'-O-glucoside, an active component of is a potent and selective arginase inhibitor. Rhubarb, activates endothelial nitric oxide (NO) nor-NOHA monoacetate inhibits rat liver arginase synthase through inhibition of arginase activity with a Ki of 0.5 µM. with IC50s of 11.22 µM and 11.06 µM against arginase I and arginase II, respectively. Purity: 99.33% Purity: ≥99.0% Clinical Data: No Development Reported Clinical Data: No Development Reported Size: 10 mM × 1 mL, 5 mg, 10 mg, 25 mg, 50 mg, 100 mg Size: 1 mg www.MedChemExpress.com 5 Aryl Hydrocarbon Receptor AhR Aryl Hydrocarbon Receptor (AhR or AHR) is a cytoplasmic receptor and transcription factor that belongs to the family of basic helix-loop-helix transcription factors. The AhR is activated or inhibited by various types of exogenous and endogenous ligands. AhR is an important factor in immunity and tissue homeostasis, and structurally diverse compounds from the environment, diet, microbiome, and host metabolism can induce AhR activity, such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Endogenous ligands include indigoids, heme metabolites, eicosanoids, tryptophan derivatives, and equilenin. Exogenous ligands include polycyclic aromatic hydrocarbons, polychlorinated biphenyls, natural compounds, and small molecule compounds. The different structures and properties of AhR ligands mean that when they combine with AhR they have distinct biological effects. Unliganded AHR is sequestered in the cytoplasm by chaperone proteins including Hsp90, AHR-interacting protein (AIP), and p23. Upon ligand binding, AHR translocates to the nucleus and heterodimerizes with ARNT. The AHR-ARNT complex regulates transcription by binding with high affinity to specific DNA sequences termed aryl hydrocarbon response elements located in the regulatory regions of target genes including CYP1A1, CYP1B1, and TIPARP. 6 Tel: 609-228-6898 Fax: 609-228-5909 Email: [email protected] Aryl Hydrocarbon Receptor Inhibitors, Agonists, Antagonists, Activators & Modulators 1,4-Chrysenequinone AHR antagonist 1 (Chrysene-1,4-dione) Cat. No.: HY-111441 Cat. No.: HY-111449 1,4-Chrysenequinone, a polycyclic aromatic AHR antagonist 1 is an aryl hydrocarbon receptor quinone, acts as an activator of aryl hydrocarbon (AHR) antagonist extracted from patent receptor (AhR). WO2017202816A1, example 23, has an IC50 of 39.9 nM in human cell line. Purity: ≥93.0% Purity: 99.07% Clinical Data: No Development Reported Clinical Data: No Development Reported Size: 10 mM × 1 mL, 50 mg Size: 10 mM × 1 mL, 5 mg, 10 mg, 25 mg, 50 mg,