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. 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 3 • STING 99 • Aryl Hydrocarbon Receptor 6 • Thrombopoietin Receptor 102 • CCR 9 • Toll-like Receptor (TLR) 104 • CD73 14 • Complement System 16 • COX 19 • CXCR 32 • FKBP 37 • FLAP 39 • Galectin 41 • Histamine Receptor 43 • IFNAR 57 • Interleukin Related 59 • IRAK 64 • MyD88 67 • NO Synthase 69 • NOD-like Receptor (NLR) 73 • PD-1/PD-L1 76 • PGE synthase 79 • Reactive Oxygen Species 82 • Salt-inducible Kinase (SIK) 95 • SPHK 97 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 & Modulators Arginase inhibitor 1 BEC hydrochloride Cat. No.: HY-15775 Cat. No.: HY-19548A Bioactivity: Arginase inhibitor 1 is a potent inhibitor of human arginases I Bioactivity: BEC HCl is a slow-binding and competitive Arginase II inhibitor with Ki of 0.31 μM (ph 7.5). target: Arginase II and II with IC50s of 223 and 509 nM, respectively. [1]; In vitro: BEC HCl causes significant enhancement of NO-dependent smooth muscle relaxation in this tissue. [2] BEC HCl enhances perivascular and peribronchiolar lung… Purity: 98.00% Purity: 98.0% Clinical Data: No Development Reported Clinical Data: Phase 3 Size: 10mM x 1mL in DMSO, Size: 10mM x 1mL in Water, 5 mg, 10 mg, 50 mg, 100 mg 5 mg, 10 mg, 25 mg, 50 mg CB-1158 CB-1158 Hydrochloride (INCB01158) Cat. No.: HY-101979 (INCB01158 Hydrochloride) Cat. No.: HY-101979A Bioactivity: CB-1158 is a potent and orally bioavailable inhibitor of Bioactivity: CB-1158 Hydrochloride is a potent and orally bioavailable arginase, with IC50s of 86 and 296 nM for recombinant human inhibitor of arginase, with IC50s of 86 and 296 nM for arginase 1 and 2, respectively. recombinant human arginase 1 and 2, respectively. Purity: >98% Purity: 98.0% Clinical Data: No Development Reported Clinical Data: No Development Reported Size: 5 mg, 10 mg, 25 mg Size: 5 mg, 10 mg, 25 mg DL-Norvaline nor-NOHA acetate (2-Aminopentanoic acid) Cat. No.: HY-W010510 (Nω-hydroxy-nor-Arginine acetate) Cat. No.: HY-112885A Bioactivity: DL-Norvaline, a derivative of L-norvaline, L-norvaline is a Bioactivity: nor-NOHA acetate is a specific and reversible arginase non-competitive inhibitor of arginase. inhibitor, induces apoptosis in ARG2-expressing cells under hypoxia but not normoxia. Anti-leukemic activity, effective in endothelial dysfunction, immunosuppression and metabolism [1]. Purity: 97.0% Purity: 99.0% Clinical Data: No Development Reported Clinical Data: No Development Reported Size: 10mM x 1mL in Water, Size: 1 mg, 5 mg 5 g Piceatannol 3'-O-glucoside (Quzhaqigan) Cat. No.: HY-N2237 Bioactivity: Piceatannol 3'-O-glucoside, an active component of Rhubarb, activates endothelial nitric oxide ( NO) synthase through inhibition of arginase activity with IC50s of 11.22 µM and 11.06 µM against arginase I and arginase II, respectively. Purity: 99.0% Clinical Data: No Development Reported Size: 5 mg www.MedChemExpress.com 5 Aryl Hydrocarbon Receptor AhR Aryl Hydrocarbon Receptor (AhR or AHR or ahr or ahR) is a protein that in humans is encoded by the AHR gene. The aryl hydrocarbon receptor is a ligand-activated transcription factor involved in the regulation of biological responses to planar aromatic (aryl) hydrocarbons, and regulates xenobiotic-metabolizing enzymes such as cytochrome P450s, most notably cyp 1A1. Aryl Hydrocarbon Receptor is a member of the family of basic helix-loop-helix transcription factors. AhR binds several exogenous ligands including natural plant flavonoids, polyphenolics and indoles, as well as synthetic polycyclic aromatic hydrocarbons and dioxin-like compounds. AhR is a cytosolic transcription factor that is normally inactive, binding to several co-chaperones. Upon ligand binding to chemicals such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), the chaperones dissociate resulting in AhR translocating into the nucleus and dimerizing with ARNT (AhR nuclear translocator), leading to changes in gene transcription. 6 Tel: 609-228-6898 Fax: 609-228-5909 Email: [email protected] Aryl Hydrocarbon Receptor Inhibitors & Modulators 1,4-Chrysenequinone AHR antagonist 1 (Chrysene-1,4-dione) Cat. No.: HY-111441 Cat. No.: HY-111449 Bioactivity: 1,4-Chrysenequinone, a polycyclic aromatic quinone, acts as an Bioactivity: AHR antagonist 1 is an aryl hydrocarbon receptor (AHR) activator of aryl hydrocarbon receptor ( AhR). antagonist extracted from patent WO2017202816A1, example 23, [1] has an IC50 of 39.9 nM in human cell line . Purity: 93.0% Purity: >98% Clinical Data: No Development Reported Clinical Data: No Development Reported Size: 10mM x 1mL in DMSO, Size: 500 mg, 100 mg, 250 mg 50 mg CAY 10465 CH-223191 Cat. No.: HY-112627 Cat. No.: HY-12684 Bioactivity: CAY 10465 is a selective and high-affinity AhR agonist, with Bioactivity: CH-223191 is a potent and specific antagonist of aryl a Ki of 0.2 nM, and shows no effect on estrogen receptor (K i hydrocarbon receptor (AhR). CH-223191 blocks the binding of TCDD to AhR with an IC of 0.03 µM. >100000 nM). 50 Purity: 98.48% Purity: 98.16% Clinical Data: No Development Reported Clinical Data: No Development Reported Size: 10mM x 1mL in DMSO, Size: 10mM x 1mL in DMSO, 5 mg, 10 mg, 50 mg, 100 mg 5 mg, 10 mg, 50 mg, 100 mg, 200 mg Diosmin FICZ Cat. No.: HY-N0178 (6-Formylindolo[3,2-b]carbazole) Cat. No.: HY-12451 Bioactivity: Diosmin is a flavonoid found in a variety of citrus fruits and Bioactivity: FICZ is a potent aryl hydrocarbon receptor (AhR) agonist with also an agonist of the aryl hydrocarbon receptor ( AhR). a Kd of 70 pM. Purity: 98.0% Purity: 99.42% Clinical Data: Launched Clinical Data: No Development Reported Size: 10mM x 1mL in DMSO, Size: 10mM x 1mL in DMSO, 50 mg 1 mg, 5 mg, 10 mg, 25 mg, 50 mg GNF351 Indole-3-carbinol Cat. No.: HY-102023 (I3C; 3-Indolemethanol) Cat. No.: HY-N0170 Bioactivity: GNF351 is a full aryl hydrocarbon receptor (AHR) antagonist. Bioactivity: Indole-3-carbinol (I3C) inhibits NF-κB activity and also is GNF351 competes with a photoaffinity AHR ligand for binding to an Aryl hydrocarbon receptor ( AhR) agonist, and an inhibitor the AHR with an IC50 of 62 nM. GNF351 is minimal toxicity in of WWP1 (WW domain-containing ubiquitin E3 ligase 1). mouse or human keratinocytes [1]. Purity: 99.90% Purity: 98.0% Clinical Data: No Development Reported Clinical Data: Phase 2 Size: 5 mg, 10 mg, 25 mg, 50 mg Size: 10mM x 1mL in DMSO, 200 mg, 1 g ITE L-Kynurenine Cat.