Uses
ML 120B is a novel competitive inhibitor of ATP and i-kappa-kinase-2 (IKK2), key regulator in the survival, proliferation and apoptosis resistance of lymphoma cells.
Biological Activity
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].
in vivo
MLN120B (oral administration; 50 mg/kg; twice daily; 3 weeks) induces a reduction of shuIL-6R, marker of tumor growth, marker of tumor growth. It also leads to a rend toward prolonged survival in animals treated versus control[1].MLN120B (oral administration; 1-30 mg/kg; twice daily; 3 weeks)?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 also reduced after MLN120B administration[2].
| Animal Model: | Two-month-old female Lewis rats[2] |
| Dosage: | 30 mg/kg, 10 mg/kg, 3 mg/kg, or 1 mg/kg |
| Administration: | Oral administration; twice daily; 3 weeks |
| Result: | Protected against bone and cartilage destruction in a rat model. |
| Animal Model: | SCID mice implanted with human fetal bone chips and then INA6 cells are directly injected into mice[1] |
| Dosage: | 50 mg/kg |
| Administration: | Oral administration; twice daily; 3 weeks |
| Result: | Inhibited human multiple myeloma cell growth in vivo. |
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.
