BMS-345541

BMS-345541 is a highly selective inhibitor of the catalytic subunits of IKK-2 and IKK-1 with IC50 of 0.3 μM and 4 μM in cell-free assays, respectively.

BMS-345541 Chemical Structure

BMS-345541 Chemical Structure

CAS: 445430-58-0

Selleck's BMS-345541 has been cited by 41 publications

Purity & Quality Control

Batch: Purity: 99.91%
99.91

BMS-345541 Related Products

Choose Selective IκB/IKK Inhibitors

Cell Data

Cell Lines Assay Type Concentration Incubation Time Formulation Activity Description PMID
THP1 cells Function assay Inhibition of LPS-induced TNFalpha secretion in THP1 cells, IC50=4 μM 17197177
SF9 cells Function assay 20 μM Inhibition of purified recombinant histidine-HA-tagged IKK-beta expressed in SF9 cells at 20 uM 18702457
H460 Cytotoxicity assay 72 hrs Cytotoxicity against human H460 cells assessed as reduction in cell viability after 72 hrs by MTT assay, IC50 = 2.8 μM. 29655083
LLC Cytotoxicity assay 72 hrs Cytotoxicity against mouse LLC cells measured after 72 hrs by MTT assay, IC50 = 4.8 μM. 27886548
A549 Cytotoxicity assay 72 hrs Cytotoxicity against human A549 cells measured after 72 hrs by MTT assay, IC50 = 5.6 μM. 27886548
NCI-H1975 Cytotoxicity assay 72 hrs Cytotoxicity against human NCI-H1975 cells assessed as reduction in cell viability after 72 hrs by MTT assay, IC50 = 8 μM. 29655083
A549 Cytotoxicity assay 72 hrs Cytotoxicity against human A549 cells assessed as reduction in cell viability after 72 hrs by MTT assay, IC50 = 8.6 μM. 29655083
NCI-H1650 Cytotoxicity assay 72 hrs Cytotoxicity against human NCI-H1650 cells assessed as reduction in cell viability after 72 hrs by MTT assay, IC50 = 9.3 μM. 29655083
Jurkat Function assay Inhibition of LPS-induced TNFalpha production in Jurkat cells, EC50 = 13.3 μM. 17540562
HL7702 Cytotoxicity assay 72 hrs Cytotoxicity against human HL7702 cells assessed as reduction in cell viability after 72 hrs by MTT assay, IC50 = 15.3 μM. 29655083
NCI-H1650 Cytotoxicity assay 72 hrs Cytotoxicity against human NCI-H1650 cells measured after 72 hrs by MTT assay, IC50 = 19.9 μM. 27886548
TC32 qHTS assay qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for TC32 cells 29435139
A673 qHTS assay qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for A673 cells 29435139
DAOY qHTS assay qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for DAOY cells 29435139
Saos-2 qHTS assay qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for Saos-2 cells 29435139
BT-37 qHTS assay qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for BT-37 cells 29435139
RD qHTS assay qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for RD cells 29435139
SK-N-SH qHTS assay qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for SK-N-SH cells 29435139
BT-12 qHTS assay qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for BT-12 cells 29435139
MG 63 (6-TG R) qHTS assay qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for MG 63 (6-TG R) cells 29435139
NB1643 qHTS assay qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for NB1643 cells 29435139
OHS-50 qHTS assay qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for OHS-50 cells 29435139
Rh41 qHTS assay qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for Rh41 cells 29435139
SJ-GBM2 qHTS assay qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for SJ-GBM2 cells 29435139
SK-N-MC qHTS assay qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for SK-N-MC cells 29435139
NB-EBc1 qHTS assay qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for NB-EBc1 cells 29435139
Click to View More Cell Line Experimental Data

Biological Activity

Description BMS-345541 is a highly selective inhibitor of the catalytic subunits of IKK-2 and IKK-1 with IC50 of 0.3 μM and 4 μM in cell-free assays, respectively.
Features Allosteric IKK inhibitor with anti-inflammatory activity.
Targets
IKK2 [1]
(Cell-free assay)
IKK1 [1]
(Cell-free assay)
0.3 μM 4 μM
In vitro
In vitro

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. [1] 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. [2] 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. [3] 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 p21Cip1 expression levels. [4] 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. [5]

Kinase Assay Enzyme Assays
Assays measuring the enzyme-catalyzed phosphorylation of GST-IκBα are performed by adding enzyme (a final concentration of 0.5 μg/mL) at 30 ℃ to solutions of 100 μg/mL GST- IκBα and 5 μM [33P]ATP in 40 mM Tris HCl, pH 7.5, containing 4 mM MgCl2, 34mM sodium phosphate, 3 mM NaCl, 0.6 mM potassium phosphate, 1 mM KCl, 1 mM dithiothreitol, 3% (w/v) glycerol, and 250 μg/mL bovine serum albumin. The specific activity of [33P]ATP used in the assay is 100 Ci/mmol. After 5 min, the kinase reactions are stopped by the addition of 2× Laemmli sample buffer and heat-treated at 90 ℃ for 1 min. The samples are then loaded on to NuPAGE 10% BisTris gels. After completion of SDS-PAGE, gels are dried on a slab gel dryer. The bands are then detected using a 445Si PhosphorImager, and the radioactivity is quantified using ImageQuant software. Under these conditions, the degree of phosphorylation of GST-IκBα is linear with time and concentration of enzyme.
Cell Research Cell lines Metastatic human melanoma cells SK-MEL-5
Concentrations ~10 μM
Incubation Time 3 days
Method

1×105 cells per well are plated in six-well plates with 10% fetal bovine serum medium overnight to allow cell adhesion. Cells ae cultured in medium containing BMS-345541 for 72 hours of treatment. Cells are counted with a hemocytometer.

Experimental Result Images Methods Biomarkers Images PMID
Western blot caspase-3 (p17) / PARP / cleaved PARP IkB / p-IkB / p65 / p-p65 / p50 / p52 / Tax 18544167
Immunofluorescence NF-κB-p65 Cyclin D1 / p-Cyclin D1 28409156
In Vivo
In vivo

BMS-345541 effectively inhibits melanoma tumor growth in a dose-dependent manner. Tumor-bearing mice treated with 75 mg/kg of BMS-345541 shows effective inhibition of growth of SK-MEL-5, A375, and Hs 294T tumors by 86 %, 69% and 67%, respectively, when compared with control animals treated with vehicle alone. [3] BMS-345541 administered orally at doses of 100 mg/kg, reduces the severity of dextran sulfate sodium-induced colitis in mice with weight ratio, clinical scoring of colons, mean injury score and mean inflammation score of 0.86 (vs 0.77 of vehicle group), 1.0 (vs 2.5 of vehicle group), 5.66 (vs 8.52 of vehicle group), 6.82 (vs 12.33 of vehicle group), respectively. [6] BMS-345541 (100 mg/kg), when administered by oral gavage in water once daily beginning at the time of the first collagen immunization, inhibits clinical signs of disease in the murine CIA model (0 vs ~8 of vehicle group), accompanied by reduced paw swelling. BMS-345541 (100 mg/kg) reduces cumulative arthritis injury score from 4.4 to 0, accompanied by lower degrade of tibiotarsal joints and severity of inflammation, synovial hyperplasia, bone resorption, and cartilage erosion. No discernible injury is observed in the joints of animals, which is histologically indistinguishable from those from age-matched, disease-free control animals. BMS-345541 dose-dependently inhibits IL-1β message, with animals in the 100 mg/kg dose group showing levels comparable with those of disease-free control animals. [7]

Animal Research Animal Models Human melanoma xenografts SK-MEL-5
Dosages 75 mg/kg
Administration orally administered by gavage

Chemical Information & Solubility

Molecular Weight 255.32 Formula

C14H17N5

CAS No. 445430-58-0 SDF Download BMS-345541 SDF
Smiles CC1=CC2=C(C=C1)N=C(C3=NC=C(N23)C)NCCN
Storage (From the date of receipt)

In vitro
Batch:

Water : 58 mg/mL

DMSO : 9 mg/mL ( (35.24 mM); Moisture-absorbing DMSO reduces solubility. Please use fresh DMSO.)

Ethanol : Insoluble


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