Biological Activity
bms-345541 is a highly selective inhibitor of ikk-1 and ikk-2 with ic50 values of 4μm and 0.3μm, respectively [1].bms-345541 is a highly selective inhibitor of ikk that inhibits nf-κb-dependent transcription of pro-inflammatory cytokines both in vitro and in vivo. this specificity is proved in the assay measuring the ikk-2-catalyzed phosphorylation of gst-iκb. in this assay, bms-345541 fails to inhibit other serine/threonine and tyrosine kinases. this selectivity is also evident in cells, only the stimulus-induced phosphorylation of iκb was inhibited by bms-345541 whereas other signal transduction cascades were unaffected [1].since the ikk/ nfκb pathway is important for viability of leukemic cells and is a predictor of relapse in t-all, bms-345541 is tested in some t-all cell lines. it is found that bms-345541 can induce apoptosis and an accumulation of cells in the g2/m phase of the cell cycle. bms-345541 can be used in combination with traditional therapies to overcome resistance to chemotherapeutic agents [2].
in vivo
BMS-345541 (10 mg/kg, p.o.) results in prolonged serum drug levels, with concentrations sustained at or above 1 μM for many hours in mice. BMS-345541 dose-dependently inhibits the production of TNFα measured in the serum of animals challenged with an intraperitoneal administration of LPS[1].
BMS-345541 (0, 10, 25, and 75 mg/kg, p.o.) effectively inhibits SK-MEL-5 tumor growth in a dose-dependent manner in the mice. Tumor-bearing mice treated with 75 mg/kg of BMS-345541 show effective inhibition of growth of SK-MEL-5, A375, and Hs 294T tumors by 86±2.8%, 69±11% and 67±3.4%, respectively[2].
BMS-345541 (30 and 100 mg/kg, p.o.) is effective in blocking both clinical and histological endpoints of inflammation and injury in mice[3].
References
[1] james r. burke, mark a. pattoli, kurt r. gregor, patrick j. brassil, john f. macmaster, kim w. mcintyre, xiaoxia yang, violetta s. iotzova, wendy clarke, joann strnad, yuping qiu and f. christopher zusi. bms-345541 is a highly selective inhibitor of iκb kinase that binds at an allosteric site of the enzyme and blocks nf-κb-dependent transcription in mice. j. biol. chem. 2003, 278:1450-1456.
[2] francesca buontempo, francesca chiarini, daniela bressanin, giovanna tabellini, fraia melchionda, andrea pession, milena fini, luca m. neri, james a. mccubrey and alberto m. martelli. activity of the selective iκb kinase inhibitor bms-345541 against t-cell acute lymphoblastic leukemia. cell cycle. 2012, 11 (13): 2467-2475.
