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Purity: ≥98%
CU-CPT-8m is a novel, potent and specific antagonist of Toll-like receptor 8 (TLR8) with immunomodulatory effects. It inhibits TLR8 with an IC50 of 67 nM. Endosomal Toll-like receptors (TLR3, TLR7, TLR8, and TLR9) are highly analogous sensors for various viral or bacterial RNA and DNA molecular patterns. Nonetheless, few small molecules can selectively modulate these TLRs. CU-CPT-8m is the first human TLR8-specific small-molecule antagonists via a novel inhibition mechanism. Crystal structures of two distinct TLR8-ligand complexes validated a unique binding site on the protein-protein interface of the TLR8 homodimer. Upon binding to this new site, the small-molecule ligands stabilize the preformed TLR8 dimer in its resting state, preventing activation. CU-CPT-8m is able to suppress TLR8-mediated proinflammatory signaling in various cell lines, human primary cells, and patient specimens. These results not only suggest a novel strategy for TLR inhibitor design, but also shed critical mechanistic insight into these clinically important immune receptors.
| ln Vitro |
CU-CPT-8m is a selective TLR8 antagonist, with an IC50 of 67±10 nM and low cytotoxicity. The Kd value of CU-CPT-8m is determined to be 220 nM. CU-CPT-8m solely suppresses the proinflammatory response in the TLR8-overexpressing cells strongly confirms that CU-CPT-8m directly recognizes TLR8 in cells. It is particularly remarkable that TLR7 signaling is not impacted at doses up to 75 μM. TLR7 and TLR8 are closely related and have several similar ligands. Treatment of 1 μM CU-CPT-8m totally abolishes the rise of TNF-α and IL-8 mRNA levels produced by R848. CU-CPT-8m suppresses R848-induced TNF-α production in the differentiated THP-1 monocytes cells in a dose- dependent manner with an IC50 of 90±10 nM, which is in good agreement with its IC50 value found in HEK-Blue TLR8 cells[1].
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| References |
[1]. Zhang S, et al. Small-molecule inhibition of TLR8 through stabilization of its resting state. Nat Chem Biol. 2018 Jan;14(1):58-64.
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| Molecular Formula |
C14H12N4O
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| Molecular Weight |
252.28
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| CAS # |
125079-83-6
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| SMILES |
O=C(C1=C2N=CC=C(C3=CC=CC(C)=C3)N2N=C1)N
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
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| 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) |
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| Solubility (In Vivo) |
Solubility in Formulation 1: 2.5 mg/mL (9.91 mM) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), suspension solution; with heating and sonication.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 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: 1.25 mg/mL (4.96 mM) 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; with heating and sonication. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 12.5 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: ≥ 1.25 mg/mL (4.96 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 | 3.9638 mL | 19.8192 mL | 39.6385 mL | |
| 5 mM | 0.7928 mL | 3.9638 mL | 7.9277 mL | |
| 10 mM | 0.3964 mL | 1.9819 mL | 3.9638 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.
 CU-CPT8m potently and selectively inhibited TLR8. Crystal structure of the TLR8/CU-CPT8m complex. |
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 TLR8 inhibitors suppress the proinflammatory cytokine production in multiple human primary cells derived from different patients. |
 Proposed antagonistic mechanism of CU-CPT compounds (top) and schematic representation of domain arrangement in each TLR8 forms (bottom). TLR8 inhibitors consistently recognize an allosteric pocket on the protein-protein interface, stabilizing the inactive TLR8 dimer |
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