cgamp

cGAMP is an endogenous second messenger in metazoans and triggers interferon production in response to cytosolic DNA. It also is a STING ligand.

cGAMP disodium is a cyclic dinucleotide (CDN) found in bacteria that acts as an endogenous second messenger affecting interferon production in response to cytoplasmic DNA. cGAMP disodium cascades signals from type I interferons and other immune mediators by activating interferon gene stimulator (STING). cGAMP disodium is a potent sublingual immune adjuvant that enables better immune function (serum anti-PA neutralization and airway secretions anti-PA SIgA response).

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.

2',3'-cGAMP-C2-PPA (45) is a cyclic di-nucleotide that acts as a STING agonist (US20210015941A1). It is a drug-linker conjugate for antibody-drug conjugates (ADC) used in the targeted treatment of cancer.

2',3'-cGAMP is an endogenous cyclic dinucleotide (CDN) produced by cGAS (cGAMP synthase) in response to double-stranded DNA in the cytoplasm. It acts as a STING activator and ligand, inducing interferons (IFNs) via the TBK1/IRF3 pathway and pro-inflammatory factors via the NF-κB pathway.

SR-717 is a cGAMP analog, a non-nucleoside STING agonist that induces a "closed" activation conformation of STING. SR-717 has antitumor activity and promotes activation of immune cells and cross-presentation of antigens.

STING-IN-2 (C-170) is a potent, covalent inhibitor of STING, effectively targeting both mouse (mmSTING) and human STING (hsSTING), and is applicable for autoinflammatory disease research.

cGAMP (Cyclic GMP-AMPP) diammonium serves as an intrinsic second messenger in metazoans, initiating the production of interferons upon cytosolic DNA detection. It activates the stimulator of interferon genes (STING), subsequently triggering a signaling cascade that culminates in the synthesis of type I interferons and various immune mediators [1] [2] [3] [4].

Mal-Val-Ala-PABA-cGAMP serves as an ADC linker for attachment to STING agonists and is utilized in the synthesis of antibody-drug conjugates (ADCs) [1].

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).

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).

3',3'-cGAMP sodium salt is a STING agonist. Reduces B cell proliferation and induces apoptosis of malignant B cellsin vitro. Suppresses 5TGM1 multiple myeloma xenograft growth in immunodeficient mice, and induces leukemic regression in Eμ-TCL1 mice.

cAIMP acts as a STING agonist and has been shown to more effectively activate STING-dependent IRF and NF-κB signaling pathways in mammalian cells in vitro when compared to standard murine (DMXAA) and human (2',3'-cGAMP) STING agonists. In ex vivo experiments with human blood, cAIMP analogs can induce the production of type I interferons (IFNs) and pro-inflammatory cytokines.

cGAS-IN-4 (Compound 36) is an orally active inhibitor of cyclic GMP-AMP synthase (cGAS) with IC50 values of 32 nM for human cGAS (h-cGAS) and 5.8 nM for mouse cGAS (m-cGAS). In THP-1 cells, cGAS-IN-4 inhibits cGAMP with an IC50 of 60 nM, enhancing cellular potency. Additionally, cGAS-IN-4 exhibits anti-inflammatory effects in a mouse model of Concanavalin A-induced acute liver injury.

Enpp-1-IN-25 (Compound 30) is an ENPP1 inhibitor with an IC50 of 8.05 nM and exhibits low oral bioavailability. By inhibiting cGAMP degradation, it effectively activates the intracellular STING pathway. Enpp-1-IN-25 can enhance immune cell infiltration and type I interferon response in the tumor microenvironment, thereby increasing the antitumor efficacy of anti-PD-L1 antibodies. It is applicable for research in cancer immunotherapy.

(S)-2-(1-Ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1-(2-hydroxy-2-phenylethyl)-1H-benzo[d]imidazole-5-carboxamide (compound 4) is a STING agonist containing the crucial amide benzimidazole (ABZI) component. It consistently inhibits the binding of 3 H-cGAMP to STING, with an apparent inhibition constant (IC50) of 14 μM. This compound is applicable in tumor research.

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).

STING-IN-8 (Compound 15b) is a potent inhibitor of the stimulator of interferon genes (STING), with an IC50 value of 0.121 μM in humans and 0.033 μM in mice. This compound effectively inhibits STING signaling induced by MSA-2 or 2',3'-cGAMP, as well as the levels of immune and inflammatory cytokines in human and mouse cells. STING-IN-8 shows significant potential for research in STING-related inflammatory and autoimmune diseases.

STINGDegrader-2 (Compound SI-43) is an inhibitor and mutant-specific degrader of STING. It effectively suppresses cGAMP-induced STING activation and significantly reduces the release of IFN-β and CXCL-10. By binding to two pockets of the STING dimer, it inhibits activity and induces proteasome-independent degradation of the mutant STINGS154 and STINGM155 (DC50 values of 0.31 and 0.76 μM, respectively). STINGDegrader-2 is applicable in the study of STING-related autoimmune diseases.

ISM5939 is an orally active and selective ENPP1 inhibitor, with an IC50 value of 0.63 nM for 2,3-cGAMP degradation and 9.28 nM for ATP hydrolysis. Additionally, ISM5939 exhibits antitumor activity.

STINGagonist-43 (Compound 67) is a selective STING agonist with an EC50 of 20.53 μM. It selectively enhances the cGAMP-dependent STING pathway activation by modulating STING oligomerization. STINGagonist-43 demonstrates antitumor activity in a B16.F10 mouse melanoma model and can be utilized in cancer immunotherapy research.

diABZI-i functions as an orthogonal STING inhibitor, significantly suppressing cGAMP-induced IFNβ in PBMCs with an IC50 of 49 nM. Additionally, diABZI-i activates V155M SAVI constitutive signaling in a STINGV155M THP-1 cell model, demonstrating potent agonistic activity (EC50: 17 nM). This compound is applicable in researching monogenic autoinflammatory diseases such as SAVI.

Enpp-1-IN-26 (Compound 4e) is an ENPP1 inhibitor with an IC50 value of 0.188 μM. By preventing ENPP1 from hydrolyzing cGAMP, Enpp-1-IN-26 enhances the expression levels of IFN-β in vivo and can be used in studies on metastatic breast cancer.

Enpp-1-IN-28 is an ENPP1 inhibitor with IC50 values of 0.188 µM at the molecular level and 0.732 µM at the cellular level. By preventing ENPP1 from hydrolyzing cGAMP, Enpp-1-IN-28 enhances the expression level of IFN-β in vivo, thereby triggering a stronger innate immune response. Enpp-1-IN-28 is applicable in metastatic breast cancer research.