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].
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
