507475-17-4

Basic information

• Product Name: TPCA-1
• Synonyms: TPCA-1;2-[(Aminocarbonyl)amino]-5-(4-fluorophenyl)-3-thiophenecarboxamide;5-(4-Fluorophenyl)-2-ureidothiophene-3-carboxamide;TPCA-1(TPCA 1);3-ThiophenecarboxaMide, 2-[(aMinocarbonyl)aMino]-5-(4-fluorophenyl)-;5-(4-Fluorophenyl)-2-ureidothiophene-3-carboxamide TPCA-1;TPCA-1 IKK-2 Inhibitor IV;GW683965
• CAS NO: 507475-17-4
• Molecular Formula: C12H10FN3O2S
• Molecular Weight: 279.294
• Product Categories: NF-kB
• Mol File: 507475-17-4.mol
• Article Data: 5

Chemical Properties

• Boiling Point: 442.576°C at 760 mmHg
• Flash Point: 221.462°C
• Appearance: white to light brown/
• Density: 1.490
• Vapor Pressure: 0mmHg at 25°C
• Refractive Index: 1.686
• Storage Temp.: 2-8°C
• Solubility: DMSO: soluble5mg/mL, clear
• PKA: 13.12±0.50(Predicted)
• Stability: Stable for 2 years from date of purchase as supplied. Solutions in DMSO may be stored at -20°C for up to 3 months.
• CAS DataBase Reference: TPCA-1(CAS DataBase Reference)
• NIST Chemistry Reference: TPCA-1(507475-17-4)
• EPA Substance Registry System: TPCA-1(507475-17-4)

Safety Data

• Hazard Codes: Xn
• Statements: 22-36
• Safety Statements: 26
• WGK Germany: 3
• Hazardous Substances Data: 507475-17-4(Hazardous Substances Data)

Usage

Description

TPCA-1 (507475-17-4) is a selective inhibitor of IκB kinase 2 (IKK2) with an IC50 value of 17.9 nM. It is known for its ability to inhibit the production of pro-inflammatory cytokines in various animal models of inflammation, including arthritis. TPCA-1 also has the potential to attenuate NLRP3 inflammasome activation in THP-1 myeloid cells and suppress IL1β-induced proliferation, migration, and invasion of HeLa cells. Additionally, continuous exposure to TPCA-1 has been shown to promote the expansion of hematopoietic stem/progenitor cells (HSPCs) through improved glycolysis and limited reactive oxygen species (ROS) production.

Uses

1. Used in Cancer Treatment:
TPCA-1 is used as a direct dual inhibitor for both IKKβ (IKK-2) and STAT3 in the treatment of cancers. It inhibits STAT3 phosphorylation, DNA binding, and transactivation in vivo. The synergistic treatment of TPCA-1 with tyrosine kinase inhibitors (TKIs) can potentially be a more effective method for treating cancers.
2. Used in Inflammation Management:
TPCA-1 is used as an anti-inflammatory agent for the management of conditions such as arthritis and other animal models of inflammation. It works by inhibiting the production of pro-inflammatory cytokines, thereby reducing inflammation and associated symptoms.
3. Used in Hematopoietic Stem/Progenitor Cell Expansion:
TPCA-1 is used as a promoter of hematopoietic stem/progenitor cell (HSPC) expansion. It enhances glycolysis and limits reactive oxygen species (ROS) production, leading to the expansion of HSPCs, which can be beneficial for various medical applications, including stem cell transplantation and regenerative medicine.
4. Used in Inhibition of NLRP3 Inflammasome Activation:
TPCA-1 is used as an inhibitor of NLRP3 inflammasome activation in THP-1 myeloid cells. By attenuating this activation, TPCA-1 can help in reducing the inflammatory response and potentially contribute to the treatment of various inflammatory diseases.
5. Used in Suppression of IL1β-Induced Cellular Processes:
TPCA-1 is used to suppress IL1β-induced proliferation, migration, and invasion of HeLa cells. This application can be relevant in the context of cancer research and treatment, as it may help in understanding and controlling the behavior of cancer cells.

Biological Activity

Potent, selective inhibitor of I κ B kinase-2 (IKK-2) (IC 50 = 17.9 nM) that displays > 22-fold selectivity over IKK-1 and > 550-fold selectivity over other kinases and enzymes. Inhibits production of pro-inflammatory cytokines in vitro and in vivo and inhibits NF- κ B nuclear localisation. Reduces the severity and onset of collagen-induced arthritis; anti-inflammatory.

Biochem/physiol Actions

TPCA-1 is a potent and selective inhibitor of human IκB kinase-2 (IKK-2) with IC50 = 17.9 nM for IKK-2 compared to 400nm for IKK-1. It has been used to study inhibition of IKK-2 to prevent inflammatory mediator release in animal models of arthritis and airway inflammation.

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].

References

Podolin et al. (2005), Attenuation of murine collagen-induced arthritis by a novel, 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; Pharmacol. Exp. Ther., 312 373 Wang et al. (2021), TPCA-1 negatively regulates inflammation mediated by NF-kB pathway in mouse chronic periodontitis model; Oral Microbiol., 36 192 Unterreiner et al. (2021), Pharmacological inhibition of IKKb dampens NLRP3 inflammasome activation after priming in the human myeloid cell line THP-1; Biophys. Res. Commun., 545 177 Tao et al. (2021), IL-1b promotes cervical cancer though activating NF-κB/CCL-2; J. Exp. Pathol., 14 426 Sun et al. (2021), Continuous NF-κB pathway inhibition promotes expansion of human phenotypical hematopoietic stem/progenitor cells through metabolism regulation; Cell Res., 399 112468

InChI:InChI=1/C12H10FN3O2S/c13-7-3-1-6(2-4-7)9-5-8(10(14)17)11(19-9)16-12(15)18/h1-5H,(H2,14,17)(H3,15,16,18)

Upstream product

• 61019-14-5 2-amino-5-(4-fluorophenyl)-3-thiophenecarboxamide 
• 1189-71-5 isocyanate de chlorosulfonyle 
• 1736-67-0 4-fluorophenylacetaldehyde 
• 904294-15-1 2‐(4-fluorophenyl)cyclopropane-1,1-dicarboxylic acid dimethyl ester 
• 859204-29-8 methyl 2-amino-5-(4-fluorophenyl)thiophene-3-carboxylate 
• 354812-10-5 2-[(aminocarbonyl)amino]-5-bromo-3-thiophenecarboxamide 
• 214360-58-4 2-(4-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane 
• 14080-51-4 2-aminothiophene-3-carboxamide 
• 339365-14-9 1-(3-carbamoylthiophen-2-yl)urea 

Relevant articles and documents

Attenuation of murine collagen-induced arthritis by a novel, potent, selective small molecule inhibitor of IκB kinase 2, TPCA-1 (2-[(aminocarbonyl)amino]-5-(4-fluorophenyl)-3-thiophenecarboxamide), occurs via reduction of proinflammatory cytokines and antigen-induced T cell proliferation

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 the present study, we demonstrate that a novel, potent (IC50 = 17.9 nM), and selective inhibitor of human IKK-2, 2-[(aminocarbonyl)amino]-5-(4-fluorophenyl)-3-thiophenecarboxamide (TPCA-1), inhibits lipopolysaccharide-induced human monocyte production of TNF-α, IL-6, and IL-8 with an IC50 = 170 to 320 nM. Prophylactic administration of TPCA-1 at 3, 10, or 20 mg/kg, i.p., b.i.d., resulted in a dose-dependent reduction in the severity of murine collagen-induced arthritis (CIA). The significantly reduced disease severity and delay of disease onset resulting from administration of TPCA-1 at 10 mg/kg, i.p., b.i.d. were comparable to the effects of the antirheumatic drug, etanercept, when administered prophylactically at 4 mg/kg, i.p., every other day. Nuclear localization of p65, as well as levels of IL-1β, IL-6, TNF-α, and interferon-γ, were significantly reduced in the paw tissue of TPCA-1- and etanercept-treated mice. In addition, administration of TPCA-1 in vivo resulted in significantly decreased collagen-induced T cell proliferation ex vivo. Therapeutic administration of TPCA-1 at 20 mg/kg, but not at 3 or 10 mg/kg, i.p., b.i.d., significantly reduced the severity of CIA, as did etanercept administration at 12.5 mg/kg, i.p., every other day. These results suggest that reduction of proinflammatory mediators and inhibition of antigen-induced T cell proliferation are mechanisms underlying the attenuation of CIA by the IKK-2 inhibitor, TPCA-1.

Thiourea participation in [3+2] cycloaddition with donor-acceptor cyclopropanes: A domino process to 2-amino-dihydrothiophenes

The Yb(OTf)3-catalyzed [3+2] cycloaddition of donor-acceptor cyclopropanes with thiourea offers an efficient route to diverse 2-amino-4,5-dihydrothiophenes (up to 92% yield), in which optically active 2-amino-dihydrothiophenes can be produced f

Nf-kb inhibitors

The present invention provides a specific compound and methods for treating diseases related to the inhibition of IKK-β phosphorylation of IK.