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Purity: =98.41%
T6167923 (T-6167923) is a novel and potent inhibitor of MyD88-dependent signaling pathways with anti-inflammatory activity. It acts by binding to Toll/IL1 receptor (TIR) domain of MyD88 and disrupting the formation of MyD88 homodimer. T6167923 inhibits pro-inflammatory cytocines with IC50s of 2.7 μM, 2.9 μM, 2.66 μM and 2.66 μM for IFN-γ, IL-1β, IL-6 and TNF-α, respectively.
T6167923 is a novel, potent, and selective small molecule inhibitor of MyD88-dependent signaling pathways . It was identified through high-throughput computational screening of over 5 million drug-like compounds, followed by structure-activity relationship optimization of initial hits . T6167923 functions by directly binding to the Toll/IL-1 receptor (TIR) domain of the MyD88 adaptor protein, thereby disrupting MyD88 homodimerization—a critical step for downstream inflammatory signaling . This compound has demonstrated anti-inflammatory activity both in vitro and in vivo, including complete protection of mice from lethal Staphylococcal enterotoxin B (SEB)-induced toxic shock . It is a valuable pharmacological tool for studying innate immune responses, Toll-like receptor signaling, and MyD88-related pro-inflammatory diseases .| Targets |
T6167923 targets the MyD88 (Myeloid differentiation primary response 88) adaptor protein. It directly binds to the Toll/IL-1 receptor (TIR) domain of MyD88 and disrupts MyD88 homodimerization . The compound inhibits pro-inflammatory cytokines with the following IC50 values in peripheral blood mononuclear cells: IFN-γ (2.7 μM), IL-1β (2.9 μM), IL-6 (2.66 μM), and TNF-α (2.66 μM) .
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| ln Vitro |
In peripheral blood mononuclear cells, T6167923 (0-500 μM; 20 h) suppresses the pro-inflammatory cytokine response to staphylococcal enterotoxin B (SEB) [2]. In HEK 293T cells, T6167923 (10-500 μM; 2 hours) suppresses the production of secreted alkaline phosphatase (SEAP) [2]. T6167923 (100 μM; 16 hours) decreases the inhibitory effect on MyD88 signaling by binding to TIR proteins [2]. T6167923 (1-500 μM; 13 hours) prevents the production of full-length MyD88 homodimers [2].
In peripheral blood mononuclear cells, T6167923 (0-500 μM; 20 hours) dose-dependently inhibits the pro-inflammatory cytokine response induced by Staphylococcal enterotoxin B, with IC50 values of 2.66 μM for TNF-α, 2.7 μM for IFN-γ, 2.66 μM for IL-6, and 2.9 μM for IL-1β . In HEK 293T cells, T6167923 (10-500 μM; 2 hours) dose-dependently inhibits secreted alkaline phosphatase expression driven by MyD88-mediated NF-κB signaling, with IC50 values ranging from 40-50 μM . T6167923 (100 μM; 16 hours) specifically binds to the TIR domain protein and reduces MyD88 signaling . The compound (1-500 μM; 13 hours) inhibits full-length MyD88 homodimer formation in a concentration-dependent manner . T6167923 shows no toxicity in primary cells up to 100 μM . It also inhibits SEA-induced pro-inflammatory cytokine production . |
| ln Vivo |
When mice are treated with SEB and LPS, T6167923 (0.17 and 1 mg; once intraperitoneally) shields them from toxicity [2].
T6167923 demonstrates dose-dependent in vivo therapeutic efficacy against Staphylococcal enterotoxin B intoxication . When administered as a single intraperitoneal injection (0.17 mg and 1 mg), T6167923 completely protects mice from lethal challenge with SEB and lipopolysaccharide . Administration of a single dose of T6167923 completely protects mice from lethal SEB-induced toxic shock . |
| Enzyme Assay |
MyD88 Homodimerization Disruption Assay: The compound was tested for its ability to inhibit full-length MyD88 homodimeric formation. T6167923 at concentrations ranging from 1-500 μM was incubated for 13 hours, and the inhibition of homodimer formation was assessed . The compound specifically inhibits TIR domain-mediated dimerization of both full-length MyD88 and the recombinant TIR domain protein .
TIR Domain Binding Assessment: T6167923 (100 μM; 16 hours) was used to assess binding to the TIR protein, demonstrating that the compound directly binds to the TIR domain and reduces the inhibitory effect on MyD88 signaling . Computational Docking Model: A protein-protein dimeric docking model of the TIR domain of MyD88 was built to identify a binding site for small molecules, and computational screening of 5 million drug-like compounds led to the identification of T6167923 as a hit compound . |
| Cell Assay |
Cell viability assay[2]
Cell Types: Peripheral blood mononuclear cells Tested Concentrations: 0-500 μM Incubation Duration: 20 hrs (hours) Experimental Results: SEB response to TNF-α, INF-γ, IL-6 and IL was dose-dependently attenuated - The IC50 of 1β in peripheral blood mononuclear cells were 2.66, 2.7, 2.66 and 2.9 μM, respectively. Cell viability assay [2] Cell Types: HEK 293T cell line Tested Concentrations: 10-500 μM Incubation Duration: 2 hrs (hours) Experimental Results: Dose-dependent inhibition of lipopolysaccharide (LPS)-induced MyD88-mediated NF-kB-driven SEAP in HEK 293T cells Expression IC50 range is 40–50 μM. Cell viability assay [2] Cell Types: HEK 293T cell line Tested Concentrations: 100 μM Incubation Duration: 16 hrs (hours) Experimental Results: TIR protein specifically targets MyD88 and reduces the inhibitory effect of MyD88 signaling in a dose-dependent manner. Western Blot Analysis[2] Cell Types: MyD88 knockout HEK 293-I3A Cell Tested Concentrations: 1-500 μM Incubation Duration: 13 hrs (hours) Experimental Results: Dose-dependent inhibition of TIR domain-mediated inhibition of full-length Cell Viability and Cytokine Inhibition Assay in PBMCs: Human peripheral blood mononuclear cells were treated with T6167923 at concentrations ranging from 0-500 μM for 20 hours. Following treatment, cells were stimulated with Staphylococcal enterotoxin B, and pro-inflammatory cytokine production (TNF-α, IFN-γ, IL-6, IL-1β) was measured. The IC50 values for cytokine inhibition were calculated to be 2.66 μM (TNF-α), 2.7 μM (IFN-γ), 2.66 μM (IL-6), and 2.9 μM (IL-1β) . NF-κB Reporter Assay in HEK 293T Cells: HEK 293T cells expressing secreted alkaline phosphatase were treated with T6167923 at concentrations ranging from 10-500 μM for 2 hours. Following treatment, cells were stimulated with lipopolysaccharide to induce MyD88-mediated NF-κB-driven SEAP expression. The compound inhibited SEAP production in a dose-dependent manner with IC50 values ranging from 40-50 μM . MyD88 Homodimerization Assay: Cells were treated with T6167923 (1-500 μM; 13 hours) to assess the inhibition of full-length MyD88 homodimer formation . Toxicity Assessment: Primary cells were treated with T6167923 at concentrations up to 100 μM, and no toxicity was observed . |
| Animal Protocol |
Animal/Disease Models: 16-20 weeks old BALB/c mouse LPS enhanced model [2]
Doses: 0.17 and 1 mg Route of Administration: intraperitoneal (ip) injection; 0.17 and 1 mg once Experimental Results: The therapeutic effect on SEB poisoning is dose-dependent. Mouse Model of SEB-Induced Toxic Shock: Mice were treated with SEB and lipopolysaccharide to induce toxic shock. T6167923 was administered via intraperitoneal injection as a single dose at concentrations of 0.17 mg and 1 mg per mouse. The compound completely protected the mice from lethal intoxication. The administration of a single dose of T6167923 completely protects mice from lethal SEB-induced toxic shock . |
| Toxicity/Toxicokinetics |
T6167923 shows no toxicity in primary cells up to a concentration of 100 μM . According to product specifications, the compound is not classified as a hazardous material for transportation . All products containing T6167923 are for research and development use only, not for human or veterinary use .
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| References |
| Molecular Formula |
C17N3O3S2BRH20
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|---|---|
| Molecular Weight |
458.393
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| Exact Mass |
457.012
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| Elemental Analysis |
C, 44.54; H, 4.40; Br, 17.43; N, 9.17; O, 10.47; S, 13.99
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| CAS # |
2437475-16-4
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| Related CAS # |
2437475-16-4; 1090528-71-4
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| PubChem CID |
25648555
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| Appearance |
White to off-white solid powder
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| Density |
1.530±0.06 g/cm3(Predicted)
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| LogP |
2.5
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| Hydrogen Bond Donor Count |
1
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| Hydrogen Bond Acceptor Count |
5
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| Rotatable Bond Count |
4
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| Heavy Atom Count |
26
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| Complexity |
591
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| Defined Atom Stereocenter Count |
1
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| SMILES |
C[C@@H](C1=CC=CS1)NC(=O)N2CCN(CC2)S(=O)(=O)C3=CC(=CC=C3)Br
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| InChi Key |
PNTQVMBKHCOLQD-ZDUSSCGKSA-N
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| InChi Code |
InChI=1S/C17H20BrN3O3S2/c1-13(16-6-3-11-25-16)19-17(22)20-7-9-21(10-8-20)26(23,24)15-5-2-4-14(18)12-15/h2-6,11-13H,7-10H2,1H3,(H,19,22)/t13-/m0/s1
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| Chemical Name |
4-(3-bromophenyl)sulfonyl-N-[(1S)-1-thiophen-2-ylethyl]piperazine-1-carboxamide
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| Synonyms |
T6167923; T 6167923; T-6167923; orb1309040; SCHEMBL19501559;
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
DMSO : ~250 mg/mL (~545.39 mM)
H2O : < 0.1 mg/mL |
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.08 mg/mL (4.54 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 2.08 mg/mL (4.54 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. View More
Solubility in Formulation 3: ≥ 2.08 mg/mL (4.54 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.1815 mL | 10.9077 mL | 21.8155 mL | |
| 5 mM | 0.4363 mL | 2.1815 mL | 4.3631 mL | |
| 10 mM | 0.2182 mL | 1.0908 mL | 2.1815 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
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