| Description: |
MLN120B is a specific, ATP competitive IKKβ inhibitor with an IC50 of 60 nM. |
| Target: |
IKKβ:60 nM (IC50) |
| In Vivo: |
MLN120B (50 mg/kg, p.o.) inhibits human multiple myeloma cell growth in vivo[1]. MLN120B (12 mg/kg twice daily, p.o.) inhibits paw swelling in a dose-dependent manner and offers significant protection against arthritis-induced weight loss as well as cartilage and bone erosion. NF-κB activity in arthritic joints is reduced after MLN120B administration[2]. |
| In Vitro: |
MLN120B inhibits both baseline and tumor necrosis factor-α-induced nuclear factor-κB activation, associated with down-regulation of IκBα and p65 nuclear factor-κB phosphorylation in multiple myeloma cells. MLN120B almost completely blocks stimulation of MM.1S, U266, and INA6 cell growth, as well as IL-6 secretion from BMSCs, induced by multiple myeloma cell adherence to BMSCs[1]. MLN120B shows an inhibitory effect on LPS induced NF-κB activation in RAW267.4 cells. The IC50 values of MLN120B is 1.4, 14.8 or 27.3 µM for NF-κB2-luc2, IL8-luc2 or TNF-AIP3-luc2 reporter transfected cells, respectively[3]. |
| Cell Assay: |
Multiple myeloma cells are cultured with MLN120B, harvested, washed, and lysed using lysis buffer [50 mM Tris-HCl (pH 7.4), 150 mM NaCl, 1% NP40, 5 mM EDTA, 5 mM NaF, 2 mM Na3VO4, 1 mM phenylmethylsulfonyl fluoride, 5 μg/mL leupeptin, 5 μg/mL aprotinin]. Whole-cell lysates are subjected to Western blotting using phosphorylated IκBα, IκBα, phosphorylated p65 NF-κB, and p65 NF-κB antibodies. |
| Animal Administration: |
Human fetal long bone grafts are implanted into SCID mice (SCID-hu mice) as described previously. Approximately 4 weeks following bone implantation, 2.5×106 INA6 multiple myeloma cells in 50 μL PBS is injected directly into human bone within SCID-hu hosts. Soluble human IL-6 receptor (shuIL-6R) released from INA6 cells is assessed in mouse sera by ELISA as in our prior studies. Mice are treated orally with vehicle alone or MLN120B 50 mg/kg (twice daily) for 3 weeks after detection of measurable shuIL-6R in mouse sera. |
| References: |
[1]. Hideshima T, et all. MLN120B, a novel IkappaB kinase beta inhibitor, blocks multiple myeloma cell growth in vitro and in vivo. Clin Cancer Res. 2006 Oct 1;12(19):5887-94.
[2]. Schopf L, et al. IKKbeta inhibition protects against bone and cartilage destruction in a rat model of rheumatoid arthritis. Arthritis Rheum. 2006 Oct;54(10):3163-73.
[3]. Ansaldi D, et al. Imaging pulmonary NF-kappaB activation and therapeutic effects of MLN120B and TDZD-8. PLoS One. 2011;6(9):e25093.
[4]. Nagashima K, et al. Rapid TNFR1-dependent lymphocyte depletion in vivo with a selective chemical inhibitor of IKKbeta. Blood. 2006 Jun 1;107(11):4266-73. |
