BMS-536924

Distributor Tel: +886-2-2827-1197jimmy@new.abscience.com.tw

Biological Activity

Description	BMS-536924 is an ATP-competitive IGF-1R/IR inhibitor with IC50 of 100 nM/73 nM, modest activity for Mek, Fak, and Lck with very little activity for Akt1, MAPK1/2.
Targets	IGF-1R	IR
IC50	100 nM	73 nM [1]
In vitro	BMS-536924 also inhibits FAK and Lck with IC50 of 150 nM and 341 nM, respectively. BMS-536924 inhibits cellular proliferation and disrupts Akt and MAPK phosphorylation. [1] BMS-536924 inhibits IGF-I-stimulated IGF-1R signaling in MCF10A cells and blocks constitutive IGF-1R activity in CD8-IGF-1R-MCF10A. Preincubation of MCF10A cells with 1 μM BMS-536924 completely blocks the ability of IGF-I to stimulate IGF-1R phosphorylation. IGF-I stimulation results in increased phosphorylation of ERK1/2, GSK3β, and Akt. BMS-536924 inhibits this ligand-induced phosphorylation. Treatment of the CD8-IGF-1R-MCF10A cells with BMS-536924 results in a dose-dependent inhibition of phosphorylation with partial inhibition at 0.01 μM and 0.1 μM, but complete receptor inhibition at a concentration of 1 μM. Maximal inhibition of phosphorylated IGF-1R is observed as early as 10 minutes following incubation. BMS-536924 retains its ability to inhibit IGF-1R phosphorylation for up to 48 hours. Addition of BMS-536924 time-dependently inhibits Akt phosphorylation starting at 1 hour. By 48 hours, Akt activation is completely blocked. [2] Treatment with BMS-536924 shows antiproliferation activity in a panel of cancer cell lines including TC32, HT1080/S, SK-LMS-1, H513 and CTR cells. pIGF-1R/pIR is activated upon IGF-I/insulin stimulation and the activation is inhibited by BMS-536924 at similar potencies in Rh41 and Rh36 cell lines. The expression of programmed cell death 4 (PDCD4), cleavage of poly(ADP-ribose) polymerase (PARP) and caspase-3 are up-regulated in Rh41 cells treated with BMS-536924. [3]
In vivo	Oral administration of BMS-536924 at 100-300 mpk strongly inhibits IGR-1R Sal tumor model. Efficacy is also observed in the nonengineered Colo205 human colon carcinoma mode. Oral administration of 3 on a once a day schedule (100-300 mpk) or a twice a day schedule (50, 100 mpk) demonstrates antitumor activity in this tumor model. Oral glucose tolerance test (OGTT) shows 100 mpk (b.i.d.) causes a significant elevation in glucose levels after glucose challenge. The pharmacokinetic parameters of BMS-536924, administered orally in poly(ethylene glycol) 400 and water (80:20 v/v), are determined in mouse, rat, dog, and monkey. Good bioavailability is evident in all species. Significant nonlinear pharmacokinetics is observed in rodents at increasing p.o. dose. [1] BMS-536924 reduces the tumor xenografts volume of CD8-IGF-1R-MCF10A cells after two weeks’ treatment (100mg/kg) to 76%. [2] Oral administration of 70 mg/kg BMS-536924 significantly inhibits tumor growth (TGBC-1TKB cells) inoculated in nude mice. BMS-536924 up regulates apoptosis in xenografts tumors. The treatment doesn’t have adverse effects on the body weight of mice or the glucose levels at the time of death, suggesting tolerable toxicity. [4]
Features

Protocol(Only for Reference)

Kinase Assay: 

^[2]

IGF-I Pathway Activity	1 × 106 pBabe-MCF10A cells are seeded onto 60-mm dishes. After 24 hours, the medium is changed to serum-free medium and incubated overnight at 37 °C for 24 hours. Cells are then pre-incubated with or without 1 uM BMS-536924 for 1 hour in serum free medium followed by stimulation with IGF-I (50 ng/mL) for 10 minutes. Cell monolayers are washed twice with PBS and harvested for immunoblot analysi

Cell Assay: 

^[3]

Cell lines	TC32, HT1080/S, SK-LMS-1, H513 and CTR cells
Concentrations	10 nM - 5 μM
Incubation Time	72 hours
Method	Cell proliferation is evaluated by [3H]thymidine incorporation after exposure to BMS-536924 for 72 hours. Cells are plated at an optimized density in 96-well plates, incubated overnight at 37 °C, and then exposed to a serial dilution of the drug. After a 72-hours incubation, cells are pulsed with 4 μCi/mL [3H]thymidine for 3 hours, trypsinized, harvested onto UniFilter-96 GF/B plates; scintillation is measured on a TopCount NXT. Results are expressed as an IC50. The mean IC50 and SD from multiple tests for each cell line are calculated.

Animal Study: 

^[4]

Animal Models	TGBC-1TKB cells are subcutaneously injected into nude mice.
Dosages	70 mg/kg
Administration	Oral once daily for 2 weeks
Solubility	30% PEG400/0.5% Tween80/5% propylene glycol, 30 mg/mL

1

References

Chemical Information

Download BMS-536924 SDF

Chemical Name

Preparing Stock Solutions

Stock Solution (1ml DMSO)	1mM	10mM	20mM	30mM
Mass(mg)	0.47996	4.7996	9.5992	14.3988

Customer Reviews (7)

Click to enlarge	Rating
	Source	Breast Cancer Research 2011 13, R52. BMS-536924 purchased from Selleck
	Method	Immunofluorescence staining
	Cell Lines	MCF7/IGF1R cells
	Concentrations
	Incubation Time
	Results	We investigated the effect of IGF-1 stimulation on MCF7/IGF-1R 4-OH-TAM resistance in a structurally and physiologically relevant context by use of a modified 3D culture. Both parental MCF7 (Figure a) and MCF7/IGF-1R cells (Figure b) were responsive to E2 or IGF-1 by forming acini on Matrigel, but the response was significantly larger in MCF7/IGF-1R cells with altered a cinar morphogenesis. inhibition of IGF -1R signaling by BMS-536924 restored 4-OH-TAM sensitivity of MCF7/IGF-1R cells in 3D culture (Figure c).

Product Citations (6)

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  Heat shock protein 90-sheltered overexpression of insulin-like growth factor 1 receptor contributes to malignancy of thymic epithelial tumors. [Breinig M, et al. Clin Cancer Res 2011;17(8):2237-49]

  
  PubMed: 21372220


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  BRCA1 negatively regulates IGF-1 expression through an estrogen-responsive element-like site. [Kang HJ, et al. Cell Death Dis 2012;3:e336]

  
  PubMed: 22739988


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  Elevated insulin-like growth factor 1 receptor signaling induces antiestrogen resistance through the MAPK/ERK and PI3K/Akt signaling routes. [Zhang Y, et al. Breast Cancer Res 2011;13(3):R52]

  
  PubMed: 21595894