生物活性

• 靶点

  IKK1 IC50:4μM

  IKK2 IC50:0.3μM

• 描述BMS-345541 dose-dependently inhibits the TNF-α-stimulated phosphorylation of IκBα in THP-1 monocytic cells with an IC50 of ~4 μM. BMS-345541 inhibits lipopolysaccharide-stimulated tumor necrosis factorα, interleukin-1β, interleukin-8, and interleukin-6 in THP-1 cells with IC50 values in the 1- to 5 μM range. BMS-345541 binds in a mutually exclusive manner with respect to a peptide inhibitor corresponding to amino acids 26 - 42 of IκBα with Ser-32 and Ser-36 changed to aspartates and in a non-mutually exclusive manner with respect to ADP. BMS-345541 binds to similar allosteric sites on IKK-1 and IKK-2, which then affects the active sites of the subunits differently. BMS-345541 affects several mitotic cell cycle transitions, including mitotic entry, prometaphase to anaphase progression and cytokinesis. Adding BMS-345541 to the cells released form arrest in G-phase blocks the activation of Aurora A, B, and C, Cdk1 activation and histone H3 phosphorylation. Treatment of the mitotic cells with BMS-345541 results in precocious cyclin B1 and securin degradation, defective chromosome separation and improper cytokinesis. BMS-345541 is also found to override the spindle checkpoint in nocodazole-arrested cells. These effects are not primarily due to a direct inhibitory effect of BMS-345541 on mitotic kinases such as Cdk1, Aurora A or B, Plk1 or NEK2. BMS-345541 (10 μM) inhibits growth of Normal human epidermal melanocytes, and metastatic melanoma cells (SK-MEL-5, A375, and Hs 294T) by 96% and 99% at 72h, respectively. Application of 100 μM of BMS-345541 to SK-MEL-5 cell culture results in 87% apoptotic cells at 24 h through caspase-independent and AIF-dependent mitochondria-mediated manner. BMS-345541 treatment (10 μM) results in 76% and 95% reduction in IKK activities and NF-kB activity, as well as CXCL1 production. BMS-345541 inhibits the growth of T-cell acute lymphoblastic leukemia (T-ALL) cells line BE-13, RPMI-8402 and DND-41, all three harboring a Notch1 mutation, and T-ALL primary cells from pediatric patients, with IC50 of 2-6 μM. 5 μM BMS-345541 induces an arrest in the G2/M phase of the cell cycle in BE-13 and DND-41 cells, and sub-G1 peak increase in RPMI-8402 cells. 5 μM BMS-345541 treated for 16 h leads to an increase in apoptotic cells in all these cell, accompanied by a time-dependent cleavage of procaspase-8, procaspase-3 and poly (ADP-ribose) polymerase (PARP). BMS-34554 (5 μM) induces a time dependent dephosphorylation of IκBα and p65. T-ALL cells treated with BMS-345541 displays nuclear translocation of FOXO3a and restoration of its functions, including control of p21 expression levels. BMS-345541 inhibits the TNFα-induced expression of both ICAM-1 and VCAM-1 in human umbilical vein endothelial cells with IC50 of 5 μM.
• 细胞研究
• Cell Data

  Cell Lines	Concentration	Assay Type	Time	Activity Description	Data Sources
  SF9 cells	20 μM	Function assay	-	Inhibition of purified recombinant histidine-HA-tagged IKK-beta expressed in SF9 cells at 20 uM	18702457
  THP1 cells	-	Function assay	-	Inhibition of LPS-induced TNFalpha secretion in THP1 cells, IC50=4 μM	17197177