Background:

IC50: IMD-0354 showed anti-tumor effect on seven hematologic malignancy cells with IC50 ranged from 0.1M to 0.6 M.

IMD-0354, serving as an IKKβ inhibitor, inhibits IκBα phosphorylation in NF-κB pathway. [1]

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]

Clinical trial: So far, a phase I clinical trial of a topical formulation of IMD-0354 for treatment of atopic dermatitis had been successfully completed. [3]

参考文献:
[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.