Uses
IMD-0354 has been used to study the effect of NF-κB (nuclear factor) inhibition on differentially expressed in chondrocytes 2. It has also been used to study the role of NF-κB signaling in tumor necrosis factor-induced certain transcription factors expression using human primary fibroblasts.
Uses
IMD 0354 is an IKKβ (IKK2) inhibitor that blocks NF-κB phosphorylation (IC50 = ~250 nM) and subsequent NF-κB p65 nuclear translocation. It exhibits cardioprotective properties by decreasing expression of P-selectin and ICAM-1 in the vasculature and blocking cardiomyocyte IL-1β and MCP-1 production, resulting in suppressed neutrophil accumulation in a rat model of ischemia/reperfusion injury. IMD 0354, suppresses the growth of human breast cancer cells by inducing cell cycle arrest and apoptosis. It induces apoptosis of chronic lymphocytic leukemia cells at 1-10 μM by directly targeting the NF-κB pathway, decreasing expression of anti-apoptotic genes and increasing expression of proapoptotic genes.
Definition
ChEBI: N-[3,5-bis(trifluoromethyl)phenyl]-5-chloro-2-hydroxybenzamide is a member of benzamides.
Biological Activity
Inhibitor of I κ B kinase-2 (IKK-2, IKK- β ) that blocks NF- κ B nuclear translocation. Attenuates myocardial ischemia/reperfusion injury by decreasing expression of adhesion molecules ICAM-1 and P-selectin and inhibiting cytokine and chemokine production in cardiomyocytes. Induces G 0 /G 1 cell cycle arrest and apoptosis in HMC-1? and breast cancer cells.
Biochem/physiol Actions
IMD-0354 acts as an inhibitor by inhibiting the phosphorylation of the NF-κB (nuclear factor) and its translocation into the nucleus. It blocks IκBα phosphorylation (IC50 ~ 250 nM). Cardioprotectant, that reduces IL-1β and MCP-1 production (IC50 < 1 μM) in cardiomyocytes. IMD-0354 affects angiogenesis, which has been observed in human umbilical vein endothelial cells. It prevents tube formation and migration of the cells. In vivo studies also prove that IMD-0354 inhibits retinal vessel growth. IMD-0354 also acts as an inhibitor of Aquaporin 4 (AQP4) inhibitor (IC50 0.2μM) with no inhibitory potency to IKK-β. [4]
in vitro
imd-0354, at the concentration of less than 5 m, down-regulated the expression of nf-κb and blocked the translocation of nf-κb to the nucleus in hmc-1 cells. study from hmc-1 cells also showed that imd-0354 inhibited cell proliferation in a time and dose dependent manner. in addition, imd-0354 at the concentration of 0.5 μm inhibited the proliferation of ic-2g559 cells and ic-2v814 cells. this agent was also reported to arrest the cell cycle at the g0/g1 phase and decreased the ratio of cells in s and g2/m phases in hmc-1 cells. 1 μm imd-0354 was reported to decrease cyclin d3 expression and reduce prb phosphorylation level in a time-dependent manner in hmc-1 cells. [1]
in vivo
a study from lungs of ova-sensitized mice showed that 5 mg/kg imd-0354 significantly inhibited nf-κb, although the magnitude of inhibition is lower than that caused by 20 mg/kg imd-0354. 20 mg/kg imd-0354 ameliorated airway hyper-responsiveness and decreased the numbers of bronchial eosinophils and mucus-producing cells in ova-sensitized mice. in addition, the total numbers of cells and eosinophils was also reduced by imd-0354 in ova-sensitized mice. moreover, imd-0354 suppressed the production of th2 cytokines inclusing il-5, il-13 and eotaxin in the airways and/or lungs of ova-sensitized mice, whereas it did not alter the restoration of th1 cytokines under the same experimental conditions. [2]
IC 50
imd-0354 showed anti-tumor effect on seven hematologic malignancy cells with ic50 ranged from 0.1m to 0.6 m.
References
[1]tanaka a, konno m, muto s, kambe n, morii e, nakahata t, itai a and matsuda h. a novel nf-kappab inhibitor, imd-0354, suppresses neoplastic proliferation of human mast cells with constitutively activated c-kit receptors. blood. 2005 mar; 105(6): 2324-31.
[2]sugita a, ogawa h, azuma m, muto s, honjo a, yanagawa h, nishioka y, tani k, itai a and sone s. antiallergic and anti-inflammatory effects of a novel i kappab kinase beta inhibitor, imd-0354, in a mouse model of allergic inflammation. int arch allergy immunol. 2009; 148(3): 186-98.
[3]verstrepen l and beyaert r. receptor proximal kinases in nf-κb signaling as potential therapeutic targets in cancer and inflammation. biochem pharm. 2014; 92: 519-29.
