ifn-β

CCCP (Carbonyl Cyanide m-Chlorophenylhydrazone) is an oxidative phosphorylation (OXPHOS) inhibitor and mitochondrial proton carrier uncoupler. CCCP inhibits the activation of STING and its downstream signaling molecules TBK1 and IRF3.

4-Methoxycinnamaldehyde (p-Methoxycinnamaldehyde) is an active ingredient of Agastache rugosa.4-Methoxycinnamaldehyde has cytoprotective activity against respiratory syncytial virus (RSV) in human laryngeal carcinoma cell lines, and helps to control disease induced by RSV infection, with an IC50 of approximately 0.055 μg/mL. The IC50 was about 0.055 μg/mL.

2',3'-cGAMP sodium (2'-3'-cyclic GMP-AMP sodium) is a second messenger in cellular innate immunity, catalyzed by cGAMP synthase (cGAS) under DNA binding conditions. It binds to STING to form a dimer, inducing the production and expression of interferon-β and other cytokines.

IFN alpha-IFNAR-IN-1 hydrochloride is an inhibitor of the interaction between IFN-α and IFNAR, effectively inhibiting MVA-induced IFN-α responses by BM-pDCs with an IC50 of 2-8 μM.

AX-024 hydrochloride (AX-024 HCl) is an cytokine release inhibitor which can strongly inhibit the production of interleukin-6 (IL-6), tumor necrosis factor-α (TNFα), interferon-γ (IFN-γ), IL-10 and IL-17A.

Caerulomycin A (Caerulomycin) (Cerulomycin; Caerulomycin) is an antifungal compound. Which induces generation of T cells, enhances TGF-β-Smad3 protein signaling via suppressing interferon-γ-induced STAT1 signaling. Antifungal and antibiotic activity, and used in autoimmune diseases.

Through its effects on ULK1 and ULK2, MRT67307 blocks autophagy. MRT67307 prevents the phosphorylation of IRF3 and the production of IFN-β and increases toll-like receptor-induced IL-10 and IL-1ra secretion in macrophages. MRT67307 is a kinase inhibitor that has been shown to inhibit TBK1, MARK1-4, IKKε, and NUAK1 (IC50 values are 19, 27-52, 160, and 230 nM, respectively), the salt-inducible kinases (SIKs; IC50s =250, 67, and 430 nM for SIK1, SIK2, and SIK3, respectively) and ULK1 and ULK2 (IC50s = 45 and 38 nM, respectively).

2',3'-cGAMP (2'-3'-cyclic GMP-AMP) is a second messenger in cellular innate immunity, catalyzed by cGAMP synthase (cGAS) under DNA binding conditions. It binds to STING to form a dimer, inducing the production and expression of interferon-β and other cytokines.

ADU-S100 (MIW815) is a cyclic dinucleotide (CDN) class STING agonist that significantly induces the production of IFN-β and pro-inflammatory cytokines TNF-α, IL-6, and MCP-1, induces TBK1 and IRF3 phosphorylation, and exhibits antitumour activity.

SM-276001 is a potent, selective agonist of TLR7 and an orally active interferon (IFN) inducer.

GHN105 is an orally active STING inhibitor that suppresses STING-dependent IFN-β secretion in THP-1 human monocytes with an IC50 of 4.4 μM. In mice, GHN105 reduces serum levels of IFN-β, IL-6, and CXCL10, and alleviates colitis in a DSS-induced acute colitis mouse model. Additionally, GHN105 demonstrates favorable pharmacokinetic properties in mice, with an oral bioavailability of 43% and a half-life of 1.1 hours.

STF-1084 is an inhibitor that cannot penetrate cells and targets ectonucleotide pyrophosphatase/phosphodiesterase family member 1 (ENPP1) with an apparent Ki of 0.11 µM. It demonstrates selectivity for ENPP1 over ENPP2 and alkaline phosphatase (ALP) with apparent Kis of 5.5 and >100 µM, respectively, and does not affect a panel of 468 kinases at 1 µM. STF-1084 hinders the extracellular breakdown of cGAMP in ENPP1-overexpressing and cGAS-expressing 293T cells, with an IC50 of 0.340 µM, and enhances mRNA expression for the gene encoding IFN-β in CD14+ primary human peripheral blood mononuclear cells (PBMCs) when incubated with conditioned medium from ENPP1-overexpressing and cGAS-expressing 293T cells treated with STF-1084. In a live setting, STF-1084, when combined with ionizing radiation, elevates the proportion of tumor-associated CD11c+ cells among antigen-presenting cells (APCs) in a murine mammary cancer model (4T1).

RO8191 (CDM-3008) (CDM-3008) is an agonist of interferon (IFN) receptor.

BRD0476 is a suppressor of pancreatic β-cell apoptosis. BRD0476 inhibits interferon-gamma (IFN-γ)-induced Janus kinase 2 (JAK2) and signal transducer and activation of transcription 1 (STAT1) signaling to promote β-cell survival. BRD0476 inhibits JAK-STAT

2'2'-cGAMP is a synthetic dinucleotide (CDN) that contains non-canonical 2'5'-phosphodiester bonds. It binds to the adapter protein stimulator of interferon genes , which is a component of the innate immune response that activates the type I interferon pathway when bound to cyclic dinucleotides. 2'2-cGAMP shows weaker binding to STING than 2'3'-cGAMP but binds more strongly than 3'3'-cGAMP , cyclic di-GMP , or 3'2'-cGAMP, which bind in the micromolar range (Kds = 1.04, 1.21, or 1.61 μM, respectively). Despite weaker binding, 2'2'-cGAMP induces IFN-β production in the same concentration range as 2'3'-cGAMP (EC50s = 15.8 and 19.4 nM, respectively, in L929 cells).

CAY10748 is an agonist of stimulator of interferon genes (STING; IC50= 0.3794 μM in a competition binding assay).1It activates STING in STING-expressing, but not STING knockout, THP-1 cells (EC50s = 0.287 and >100 μM, respectively, in a reporter assay). It induces phosphorylation of STING at the serine in position 366, as well as phosphorylation of TBK1 and IFN regulatory factor 3 (IRF3), indicating activation of the STING-TBK1-IRF3 signaling pathway. CAY10748 increases the secretion of IFN-β and the levels of chemokine (C-X-C motif) ligand 10 (CXCL10), and IL-6 in peripheral blood mononuclear cells (PBMCs) when used at a concentration of 10 μM. It also reduces tumor growth in a CT26 murine colon cancer model when administered at a dose of 0.15, but not 1.5, mg/kg. 1.Xi, Q., Wang, M., Jia, W., et al.Design, synthesis, and biological evaluation of amidobenzimidazole derivatives as stimulator of interferon genes (STING) receptor agonistsJ. Med. Chem.63(1)260-282(2019)

NG 25 is a type II kinase inhibitor that inhibits MAP4K2 and TAK1 (IC50s = 21.7 and 149 nM, respectively).1It also inhibits the Src family kinases Src and LYN (IC50s = 113 and 12.9 nM, respectively) and Abl family kinases (IC50s = 75.2 nM), as well as CSK, FER, and p38α (IC50s = 56.4, 82.3, and 102 nM, respectively). NG 25 (100 nM) prevents TNF-α-induced IKKα/β phosphorylation and IκB-α degradation in L929 cells. It inhibits secretion of IFN-α and IFN-β induced by CpG type B and CL097, respectively, in Gen2.2 cells in a concentration-dependent manner.2NG 25 decreases cell viability of HCT116KRASWT, and to a greater degree of HCT116KRASG13D, colorectal cancer cells in a concentration-dependent manner.3It also reduces tumor growth and increases the number of TUNEL-positive tumor cells in a CT26KRASG12Dmouse orthotopic model of colorectal cancer. 1.Tan, L., Nomanbhoy, T., Gurbani, D., et al.Discovery of type II inhibitors of TGFβ-activated kinase 1 (TAK1) and mitogen-activated protein kinase kinase kinase kinase 2 (MAP4K2)J. Med. Chem.58(1)183-196(2015) 2.Pauls, E., Shpiro, N., Peggie, M., et al.Essential role for IKKβ in production of type 1 interferons by plasmacytoid dendritic cellsJ. Biol. Chem. 287(23)19216-19228(2012) 3.Ma, Q., Gu, L., Liao, S., et al.NG25, a novel inhibitor of TAK1, suppresses KRAS-mutant colorectal cancer growth in vitro and in vivoApoptosis24(1-2)83-94(2019)

MSA-2 dimer, a selective and orally active non-nucleotide STING agonist with a dissociation constant (Kd) of 145 μM, demonstrates prolonged antitumor and immunogenic activity. It non-covalently binds to STING as a dimer, showing greater permeability compared to cyclic dinucleotide[1].

3'3'-cGAMP is a second messenger produced in bacteria by specific dinucleotide cyclases. It contains canonical 3'5'-phosphodiester bonds and regulates chemotaxis, colonization, and other cellular functions. 3'3'-cGAMP shows weaker binding to the adapter protein stimulator of interferon genes (STING; Kd = 1.04 μM) than 2'2'-cGAMP and 2'3'-cGAMP but has similar binding affinity to 3'2'-cGAMP (Kd = 1.61 μM) and cyclic di-GMP . 3'3'-cGAMP induces IFN-β mRNA expression in L929 cells (EC50 = 40.5 nM).

StA-IFN-1 is an inhibitor of the interferon (IFN) induction pathway with an IC50 value of 4.1 μM in a GFP reporter assay for IFN induction similar to TPCA-1 , which specifically inhibits the IKKβ component of the IFN induction pathway. It does not show inhibitory activity in a GFP reporter assay for IFN signaling in which ruxolitinib , which is specific for the IFN signaling component JAK1, is active. StA-IFN-1 reduces the levels of IFN-β, but not ISG MxA, mRNA, suggesting that it is selective for the IFN induction pathway and not the IFN signaling pathway.

STING agonist 1a is an agonist of stimulator of interferon genes (STING).1It induces expression of an IRF-inducible SEAP reporter gene in a cell-based assay (EC50= 16.77 μM). STING agonist 1a (12.5-100 μM) induces expression of IFN-β, IL-6, and chemokine (C-X-C motif) ligand 10 (CXCL10) in THP-1 cells, an effect that can be reversed by STING knockout or the STING inhibitor H-151 . 1.Hou, H., Yang, R., Liu, X., et al.Discovery of triazoloquinoxaline as novel STING agonists via structure-based virtual screeningBioorg. Chem.100103958(2020)

STING agonist C11 is an agonist of the stimulator of interferon genes (STING) pathway.1 It induces secretion of type I IFN from THF and MM6 cells when used at a concentration of 50 μM. STING agonist C11 induces phosphorylation of IFN regulatory factor 3 (IRF3) and increases expression of IFIT1 and viperin, but not IL-1β, IL-6, or IL-8 in THF cells in a STING-dependent manner. It reduces viral titers of chikungunya, Venezuelan equine encephalitis, o'nyong-nyong, Mayaro, and Ross River viruses grown in THF cells (EC90s = 16.44, 16.7, 18.84, 25.19, and 22.57 μM, respectively), an effect that is dependent on the presence of STING and the IFN-α/β receptor (IFNAR).References1. Gall, B., Pryke, K., Abraham, J., et al. Emerging alphaviruses are sensitive to cellular states induced by a novel small-molecule agonist of the STING pathway. J. Virol. 92(6), e01913-01917 (2018). STING agonist C11 is an agonist of the stimulator of interferon genes (STING) pathway.1 It induces secretion of type I IFN from THF and MM6 cells when used at a concentration of 50 μM. STING agonist C11 induces phosphorylation of IFN regulatory factor 3 (IRF3) and increases expression of IFIT1 and viperin, but not IL-1β, IL-6, or IL-8 in THF cells in a STING-dependent manner. It reduces viral titers of chikungunya, Venezuelan equine encephalitis, o'nyong-nyong, Mayaro, and Ross River viruses grown in THF cells (EC90s = 16.44, 16.7, 18.84, 25.19, and 22.57 μM, respectively), an effect that is dependent on the presence of STING and the IFN-α/β receptor (IFNAR). References1. Gall, B., Pryke, K., Abraham, J., et al. Emerging alphaviruses are sensitive to cellular states induced by a novel small-molecule agonist of the STING pathway. J. Virol. 92(6), e01913-01917 (2018).

STING18 is a competitive ligand of stimulator of interferon genes (STING; IC50 = 0.068 μM in a radioligand binding assay).1 It inhibits cGAMP-induced IFN-β production (IC50 = 11 μM) but does not stimulate IFN-β production (EC50 = >30 μM) in THP-1 cells. |1. Siu, T., Altman, M.D., Baltus, G.A., et al. Discovery of a novel cGAMP competitive ligand of the inactive form of STING. Med. Chem. Lett. 10(1), 92-97 (2019).

CU-32 is an inhibitor of cyclic GMP-AMP (cGAMP) synthase (cGAS; IC50= 0.45 μM).1It reduces DNA-, but not Sendai virus-, induced dimerization of IFN regulatory factor 3 in THP-1 cells, indicating selectivity for the cGAS DNA sensing pathway over the RIG-I-MAVS RNA sensing pathway. It is also selective for cGAS over toll-like receptors (TLRs) at 50 μM. CU-32 decreases IFN-stimulatory DNA-induced production of IFN-β in THP-1 cells when used at concentrations of 10, 30, and 100 μM. 1.Padilla-Salinas, R., Sun, L., Anderson, R., et al.Discovery of small-molecule cyclic GMP-AMP synthase inhibitorsJ. Org. Chem.85(3)1579-1600(2020)