Description
TPCA-1 (507475-17-4) selective inhibitor of IκB kinase 2 (IKK2) (IC50 = 17.9 nM).1 Inhibits production of pro-inflammatory cytokines in arthritis and other animal models of inflammation.1,2 Also attenuates NLRP3 inflammasome activation in THP-1 myeloid cells, and suppresses IL1β-induced proliferation, migration, and invasion of HeLa cells.3,4 Continuous exposure to TPCA-1 promotes expansion of hematopoietic stem/progenitor cells (HSPCs) via improved glycolysis and limited ROS production.5
Uses
TPCA-1 is a direct dual inhibitor for both IKKβ (IKK-2) and STAT3. It inhibits STAT3 phosphorylation, DNA binding, and transactivation in vivo. Synergistic treatment of TPCA-1 with tyrosine kinase inhibitors (TKIs) can potentially be a more effective method for treating cancers.
Definition
ChEBI: 2-(carbamoylamino)-5-(4-fluorophenyl)-3-thiophenecarboxamide is a member of thiophenes and an aromatic amide.
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].
Background
TPCA-1 blocks NF-κB signaling and suppresses the transcription of several pro-inflammatory cytokines through inhibition of the IκB kinase subunit IKKβ. Studies show that TPCA-1 specifically inhibits IKKβ and reduces inflammation and antigen-induced T cell proliferation in murine collagen-induced arthritis. TPCA-1 prevents recruitment of the transcription factor STAT3 to upstream kinases through interaction with the SH2 domain of STAT3. This limits the ability of cytokines and tyrosine kinases to induce STAT3 activity, which inhibits the ability of STAT3 to regulate cell growth and apoptosis. Treatment of non-small cell lung cancer cells with TPCA-1 represses cell proliferation, suggesting that TPCA-1 may be effective in treating some forms of cancer. Studies have examined the ability of TPCA-1 to mediate the inflammatory response through control of IKKβ and STAT3 signaling in animal models of arthritis, chronic periodontitis, and nasal epithelial inflammation.
References
[1] PATRICIA L PODOLIN. 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]. Journal of Pharmacology and Experimental Therapeutics, 2005, 312 1: 373-381. DOI:
10.1124/jpet.104.074484[2] BO WANG. TPCA-1 negatively regulates inflammation mediated by NF-κB pathway in mouse chronic periodontitis model.[J]. Molecular Oral Microbiology, 2021: 192-201. DOI:
10.1111/omi.12335[3] ADELINE UNTERREINER . Pharmacological inhibition of IKKβ dampens NLRP3 inflammasome activation after priming in the human myeloid cell line THP-1[J]. Biochemical and biophysical research communications, 2021, 545: Pages 177-182. DOI:
10.1016/j.bbrc.2021.01.051[4] LIMIN TAO. IL-1β promotes cervical cancer through activating NF-κB/CCL-2.[J]. International journal of clinical and experimental pathology, 2021, 14 4: 426-433.
[5] QIHAO SUN. Continuous NF-κB pathway inhibition promotes expansion of human phenotypical hematopoietic stem/progenitor cells through metabolism regulation[J]. Experimental cell research, 2021, 399 2: Article 112468. DOI:
10.1016/j.yexcr.2020.112468
