MLN120B is a potent and effective inhibitor of IκB kinase beta subunit (IKKβ) with IC50 value of 20 μM [1].
IKK is an enzyme complex which is a part of the upstream of NF-κB signal transduction cascade. It is composed of three subunits, including IKKα, IKKβ and IKKγ. The IKKβ subunit is able to phosphorylate IκBα protein. Normally, IκBα protein inactivate NF-κB transcription factors and keep them sequestering in inactive state in the cytoplasm. However, once IκBα protein is phosphorylated by IKKβ subunit, the IκBα protein will be dissociated from NF-κB transcription factor and thus remove the inactivation effect. Therefore, the transcription of NF-κB will be activated. This signaling pathway is involved in many immune and inflammatory processes.
In multiple myeloma cell line RPMI 8226 and INA 6, treatment of MLN120B resulted in the dose-dependent inhibition of IKKβ-induced IκBα protein phosphorylation and subsequent NF-κB activation. Additionally, it was observed that MLN120B was able to block TNF-α-induced NF-κB activation in MM.1S cell line. These observations suggested the inhibitory action of MLN120B on IKKβ. [1].
In mouse model, polyarthritis was introduced in footpads, where IKKβ-induced NF-κB activation might result in a serial of advert effects. Oral administration of MLN120B (12 mg/kg twice daily) inhibited paw swelling in a dose-dependent manner, and offered protection against arthritis-induced weight loss. Therefore, it could be implied that MLN120B was able to inhibit IKKβ-induced NF-κB activation [2].
References:
[1]. Hideshima T, Neri P, Tassone P. MLN120B, a novel IkappaB kinase beta inhibitor, blocks multiple myeloma cell growth in vitro and in vivo. Clin Cancer Res. 2006, 12(19): 5887-5894.
[2]. Schopf L, Savinainen A, Anderson K. IKKbeta inhibition protects against bone and cartilage destruction in a rat model of rheumatoid arthritis. Arthritis Rheum. 2006, 54(10): 3163-3173.