WARNING: This product is for research use only, not for human or veterinary use.
MedKoo CAT#: 555342
Description: C-176 (C-176) is a covalent, in vivo-active, small-molecule inhibitor of STING, attenuates STING-associated autoinflammatory disease in mice.
MedKoo Cat#: 555342
Name: C-176 STING inhibitor
Chemical Formula: C11H7IN2O4
Exact Mass: 357.945
Molecular Weight: 358.0915
Elemental Analysis: C, 36.90; H, 1.97; I, 35.44; N, 7.82; O, 17.87
Synonym: STING inhibitor C-176; C-176, C176; C 176
IUPAC/Chemical Name: N-(4-iodophenyl)-5-nitrofuran-2-carboxamide
InChi Key: JBIKQXOZLBLMKI-UHFFFAOYSA-N
InChi Code: InChI=1S/C11H7IN2O4/c12-7-1-3-8(4-2-7)13-11(15)9-5-6-10(18-9)14(16)17/h1-6H,(H,13,15)
SMILES Code: O=C(C1=CC=C([N+]([O-])=O)O1)NC2=CC=C(I)C=C2
Appearance: Solid powder
Purity: >98% (or refer to the Certificate of Analysis)
Shipping Condition: Shipped under ambient temperature as non-hazardous chemical. This product is stable enough for a few weeks during ordinary shipping and time spent in Customs.
Storage Condition: Dry, dark and at 0 - 4 C for short term (days to weeks) or -20 C for long term (months to years).
Solubility: Soluble in DMSO
Shelf Life: >3 years if stored properly
Drug Formulation: This drug may be formulated in DMSO
Stock Solution Storage: 0 - 4 C for short term (days to weeks), or -20 C for long term (months).
HS Tariff Code: 2934.99.03.00
|Biological target:||C-176 is a strong and covalent mouse STING inhibitor.|
|In vitro activity:||To discover molecules that inhibit STING, a cell-based chemical screen was performed and the nitrofuran derivative C-176 was identified to strongly reduce STING-mediated, but not RIG-I- or TBK1-mediated, IFNß reporter activity (Fig. 1a, b and Extended Data Fig. 1a-d). Celluar washout experiments, native mass spectrometry assays on mmSTING (wild type and STING(C91S)) and top-down liquid-chromatography tandem mass spectrometry (LC-MS/MS) together confirmed that the Cys91 of mmSTING is covalently modified by C-176 (Fig. 2c, Extended Data Fig. 3 and Supplementary Information). It was found that within living cells C-176-AL, a C-176 derivative, effectively and specifically labelled mmSTIN G, whereas neither hsSTIN G nor mmSTING with a Cys91 substitution (either STING(C91A) or STING(C91S)) were targeted by the clickable compound (Fig. 2d, e and Extended Data Fig. 4c-e). The gel-based protein profiling approach was used to study the degree of molecular selectivity in the covalent interaction between the compounds and STING. When compared to iodoacetamide azide, which is a non-specific cross-linking probe, an azide-based clickable C-176 probe (C-176-AZ) showed markedly lower background proteome reactivity (Extended Data Fig. 4f). Furthermore, testing STING against a panel of proteins that contain hyper-reactive cysteine residues revealed that only STING was efficiently labelled by C-176-AZ23,24 (Extended Data Fig. 4g). It was also noted that the installation of an additional methyl group at the central amine moiety of C-176 completely abolished the inhibitory capacity of the compound (Extended Data Fig. 1e, f). Reference: Nature. 2018 Jul;559(7713):269-273. https://doi.org/10.1038/s41586-018-0287-8|
|In vivo activity:||The effects of pharmacological inhibition of STING in mice were studied with C-176. First it was verified that the compounds target STING by using an in vivo click-chemistry approach and the pharmacokinetic profile of C-176 on single-dose intraperitoneal injection (Extended Data Fig. 6a, b). We next evaluated whether C-176 can suppress the induction of type I IFNs triggered by the administration of CMA was assessed. Of note, pretreatment with C-176 markedly reduced the CMA-mediated induction of serum levels of type I IFNs and IL-6. (Fig. 4a and Extended Data Fig. 6c). Thus, C-176 is effective in mice and-as expected for a covalent inhibitor- the short serum half-life does not limit its in vivo inhibitory capacity. To assess the potential of C-176 to antagonize STING in a model of autoinflammatory disease, its efficacy in Trexl-/mice was investigated. Trexl-l - mice show signs of severe multi-organ inflammation caused by the persistent activation of the cyclic GMP-AMP synthase-STING pathway and recapitulate certain pathogenic features of Aicardi-Goutieres syndrome in humans. Having verified that C-178 suppresses interferon-stimulated genes in cells from Trexl - mice (Extended Data Fig. 7a), a two-week in vivo efficacy study with C-176 was performed. Notably, treatment of Trexl ~- mice with C-176 resulted in a significant reduction in serum levels of type I IFNs and in a strong suppression of inflammatory parameters in the heart (Extended Data Fig. 7b, c). Wild-type mice on a two-week treatment with C-176 showed no evident signs of overt toxicity (Extended Data Fig. 6d-g). A three-month trial with C-176 in Trexl4 – mice was conducted, which demonstrated marked amelioration of various signs of systemic inflammation (Fig. 4b, c and Extended Data Fig. 7e). Thus, C-176 attenuates STING-associated autoinflammatory disease in mice. Reference: Nature. 2018 Jul;559(7713):269-273. https://doi.org/10.1038/s41586-018-0287-8|
|Solvent||Max Conc. mg/mL||Max Conc. mM|
The following data is based on the product molecular weight 358.0915 Batch specific molecular weights may vary from batch to batch due to the degree of hydration, which will affect the solvent volumes required to prepare stock solutions.
|Concentration / Solvent Volume / Mass||1 mg||5 mg||10 mg|
|1 mM||1.15 mL||5.76 mL||11.51 mL|
|5 mM||0.23 mL||1.15 mL||2.3 mL|
|10 mM||0.12 mL||0.58 mL||1.15 mL|
|50 mM||0.02 mL||0.12 mL||0.23 mL|
|In vitro protocol:||1. Haag SM, Gulen MF, Reymond L, Gibelin A, Abrami L, Decout A, Heymann M, van der Goot FG, Turcatti G, Behrendt R, Ablasser A. Targeting STING with covalent small-molecule inhibitors. Nature. 2018 Jul;559(7713):269-273. doi: 10.1038/s41586-018-0287-8. Epub 2018 Jul 4. PMID: 29973723.|
|In vivo protocol:||1. Haag SM, Gulen MF, Reymond L, Gibelin A, Abrami L, Decout A, Heymann M, van der Goot FG, Turcatti G, Behrendt R, Ablasser A. Targeting STING with covalent small-molecule inhibitors. Nature. 2018 Jul;559(7713):269-273. doi: 10.1038/s41586-018-0287-8. Epub 2018 Jul 4. PMID: 29973723.|