TPCA-1
TPCA-1 is a novel, potent, and selective inhibitor of human IKK-2.
Demonstration that IκB kinase 2 (IKK-2) plays a pivotal role in the nuclear factor-κB-regulated production of proinflammatory molecules by stimuli such as tumor necrosis factor (TNF)-α and interleukin (IL)-1 suggests that inhibition of IKK-2 may be beneficial in the treatment of rheumatoid arthritis.
In vitro: Determination of the activity of TPCA-1 against ten selected kinases, COX-1 and COX-2, showed the compound to be ~550-fold selective for IKK-2 versus ten of these enzymes. TPCA-1 inhibits lipopolysaccharide-induced human monocyte production of TNF-α, IL-6, and IL-8 with an IC50 of 170 to 320 nM [1].
In vivo: Prophylactic administration of TPCA-1 at 3, 10, or 20 mg/kg resulted in a dose dependent reduction in the severity of murine collagen-induced arthritis. The significantly reduced disease severity and delay of disease onset resulting from administration of TPCA-1 at 10 mg/kg were comparable to the effects of the antirheumatic drug, etanercept [1].
Clinical trial: No clinical data are available currently.
Reference:
[1] Podolin PL, Callahan JF, Bolognese BJ, Li YH, Carlson K, Davis TG, Mellor GW, Evans C, Roshak AK. Attenuation of murine collagen-induced arthritis by a novel, potent, selective small molecule inhibitor of IkappaB Kinase 2, TPCA-1 (2-[(aminocarbonyl)amino]-5-(4-fluorophenyl)-3 -thiophenecarboxamide), occurs via reduction of proinflammatory cytokines and antigen-induced T cell Proliferation. J Pharmacol Exp Ther. 2005 Jan;312(1):373-81.
- 1. Yanhong Chen, Xu Zhou, et al. "The miR-26a-5p/IL-6 axis alleviates sepsis-induced acute kidney injury by inhibiting renal inflammation." Ren Fail. 2022 Dec;44(1):551-561. PMID: 35491874
- 2. Jingchun Du, Yougui Xiang, et al. "RIPK1 dephosphorylation and kinase activation by PPP1R3G/PP1γ promote apoptosis and necroptosis." Nat Commun. 2021 Dec 3;12(1):7067. PMID: 34862394
- 3. Varga Z, Molnár T, et al. "Differences in the sensitivity of classically and alternatively activated macrophages to TAK1 inhibitor-induced necroptosis." Cancer Immunol Immunother. 2020;10.1007/s00262-020-02623-7. PMID: 32472370
- 4. Robert J. Posont. "The Role of Inflammatory Pathways in Development, Growth, and Metabolism of Skeletal Muscle in IUGR Offspring; Blood Gene Expression of Inflammatory Factors as Novel Biomarkers for Assessing Stress and Wellbeing in Exotic Species." University of Nebraska-Lincoln. 2019.
- 5. Robeson AC, Lindblom KR, et al. "Dimer-specific immunoprecipitation of active caspase-2 identifies TRAF proteins as novel activators." EMBO J. 2018 Jun 6. pii: e97072. PMID: 29875129
- 6. Kwon Y, Choi SK, et al. "Involvement of inhibitor kappa B kinase 2 (IKK2) in the regulation of vascular tone." Lab Invest. 2018 May 21. PMID: 29785049
| Physical Appearance | A solid |
| Storage | Desiccate at -20°C |
| M.Wt | 279.29 |
| Cas No. | 507475-17-4 |
| Formula | C12H10FN3O2S |
| Solubility | insoluble in H2O; ≥13.95 mg/mL in DMSO; ≥2.53 mg/mL in EtOH with gentle warming and ultrasonic |
| Chemical Name | 2-(carbamoylamino)-5-(4-fluorophenyl)thiophene-3-carboxamide |
| SDF | Download SDF |
| Canonical SMILES | C1=CC(=CC=C1C2=CC(=C(S2)NC(=O)N)C(=O)N)F |
| Shipping Condition | Small Molecules with Blue Ice, Modified Nucleotides with Dry Ice. |
| General tips | We do not recommend long-term storage for the solution, please use it up soon. |
| Cell experiment [1]: | |
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Cell lines |
Human Monocytes |
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Preparation method |
The solubility of this compound in DMSO is >14mg/mL. General tips for obtaining a higher concentration: Please warm the tube at 37℃ for 10 minutes and/or shake it in the ultrasonic bath for a while. Stock solution can be stored below -20℃ for several months. |
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Reacting condition |
0.1, 0.3, 1, 3 and 10 μM; 30 min |
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Applications |
In human peripheral blood monocytes, TPCA-1 inhibited the production of TNF-α, IL-6, and IL-8 induced by LPS in a concentration-dependent way with IC50 values of 170, 290, and 320 nM, respectively. |
| Animal experiment [1]: | |
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Animal models |
collagen-immunized/boosted DBA/1 mice |
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Dosage form |
3, 10, or 20 mg/kg, i.p., b.i.d., from days 1 to 48. |
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Application |
In collagen-immunized/boosted DBA/1 mice, TPCA-1 (20 or 10 mg/kg) dose-dependently reduced the severity of arthritis, resulting in a significantly decreased mean clinical score and delaying time to onset of disease. TPCA-1 (10 mg/kg, i.p., b.i.d.) also inhibited p65 nuclear localization and paw tissue levels of IL-1β, IL-6, TNF-α, and IFN-γ. |
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Other notes |
Please test the solubility of all compounds indoor, and the actual solubility may slightly differ with the theoretical value. This is caused by an experimental system error and it is normal. |
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References: [1] Podolin PL, Callahan JF, Bolognese BJ, Li YH, Carlson K, Davis TG, Mellor GW, Evans C, Roshak AK. Attenuation of murine collagen-induced arthritis by a novel, potent, selective small molecule inhibitor of IkappaB Kinase 2, TPCA-1 (2-[(aminocarbonyl)amino]-5-(4-fluorophenyl)-3 -thiophenecarboxamide), occurs via reduction of proinflammatory cytokines and antigen-induced T cell Proliferation. J Pharmacol Exp Ther. 2005 Jan;312(1):373-81. |
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| Description | TPCA-1 is a selective inhibitor of IκB kinase-2 with IC50 values of 17.9 nM and 0.4 μM for IKK-2 and -1, respectively. | |||||
| Targets | IKK-2 | IKK-1 | ||||
| IC50 | 17.9 nM | 0.4 μM | ||||
Quality Control & MSDS
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