BMS-536924

Catalog No.S1012 Synonyms: HY-10262, CS-0117

BMS-536924 Chemical Structure

Molecular Weight(MW): 479.96

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.

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Cited by 12 Publications

9 Customer Reviews

  • A, cell viability reduction. TC1889 cells were treated with pharmacological inhibitors against IGF-1R (NVP and BMS), as well as a neutralizing IGF-1R antibody (aIR3) and cell viability was assessed using MTT-assays. Mouse IgG1 antibody was employed as a reference control for the effects of aIR3 at respective concentrations. Assays were performed in sextuple. Data are expressed as the mean SD (n 3). B, induction of cell death. TC1889 cells were treated with pharmacological inhibitors against IGF-1R as well as a neutralizing IGF-1R antibody and cell death was evaluated by FACS-analyses following PI-staining. Data are expressed as the mean SD (n =3).

    Clin Cancer Res 2011 17, 2237-2249. BMS-536924 purchased from Selleck.

    C, TC1889 cells were serum-starved for 16 hours, treated with vehicle or the IGF-1R inhibitor PPP, NVP, BMS, or the neutralizing IGF1R antibody aIR3 for 2 hours, and then stimulated with IGF-I (100 ng/mL) for 15 min. The activity of PI3K/Akt- and MAPK/Erk-signaling was investigated by an analysis of the expression of phosphorylated Akt, GSK3b, MEK1/2, and Erk using Western immunoblotting. Representative results are shown (n ?3). Actin served as a loading control. D, TC1889 cells were treated with vehicle or PPP, NVP, BMS, or aIR3. The activity of PI3K/Akt- and MAPK/Erk-signaling was investigated as mentioned earlier. Representative results are shown (n=3). Actin served as a loading control.

     

     

    Clin Cancer Res 2011 17, 2237-2249. BMS-536924 purchased from Selleck.

  • Three-dimensional responses of MCF7/IGF-1R cells to TAM (1 μM), E2 and IGF-1. Compared to parental MCF7 cells (a), MCF7/IGF-1R cells (b) in three-dimensional (3D) culture formed bigger acini in response to IGF-1 stimulation and displayed significant TAM resistance when treated with TAM (1 μM) + E2 + IGF-1, which was removable by kinase inhibitors BMS-536924, U0126 and BEZ235 (c). Cells (10,000/well) were seeded in 96-well plates. Acini were formed on 100% Matrigel and cultured for 14 days in starving medium containing 2% Matrigel and 5% charcoal/dextran-stripped fetal bovine serum with the treatments as indicated. Concentrations used: TAM (1 μM), E2 (1 nM) and IGF-1 (100 ng/mL). Confocal image original magnification, × 20. Red, rhodamine phalloidin (actin). Blue, Hoechst blue stain. Results are representative of two individual experiments.

    Breast Cancer Res 2011 13, R52. BMS-536924 purchased from Selleck.

    TAM (10 nM) agonistic behavior in MCF7/IGF-1R cells is not inhibited by phosphatidylinositol 3-kinase/Akt inhibitor BEZ235. (a) Inhibitory effects of kinase inhibitors BMS-536924, U0126 and BEZ235 on agonistic effect of TAM (10 nM) in the presence of IGF-1 (100 ng/mL). **P < 0.01. (b) Inhibitory effects of phosphatidylinositol 3-kinase (PI3K)/Akt inhibitor BEZ235 at various dose ranges on IGF-1R signaling. (c) Agonistic behavior of TAM (10 nM) in response to BEZ235 kinase inhibitor. (-), no BEZ235. Results are representative of three independent experiments. Data are expressed as means ± SD.

    Breast Cancer Res 2011 13, R52. BMS-536924 purchased from Selleck.

  • Inhibition of signaling pathway activation in lung tumor cell lines by kinase inhibitors. Lung tumor cells were cultured in 10% FBS until reaching ∼80% confluence and then the cells were starved in serum-free medium for overnight, followed by 4-hour treatment with the inhibitors. Cell lysates were then prepared and used for determination of the pathway activation signals by the CEER assay.

    Int J Proteomics 2011 2011, 215496. BMS-536924 purchased from Selleck.

    Inhibition of anchorage-independent growth of lung tumor cell lines by selected inhibitors. Each selected cell line was treated with the indicated inhibitor at 0.1 μM and 1 μM concentrations for two weeks and cell colony size formation was scored under the Nikon inverted-phase microscope.

    Int J Proteomics 2011 2011, 215496. BMS-536924 purchased from Selleck.

  • Effect of IGF-1R kinase inhibitor on IGF-1R signaling. IGF-1R overexpressing MCF-10A cells were treated in suspension cultures containing IGF-1 (100ng/ml) for 48 hours with the indicated concentrations of IGF-1 receptor kinase inhibitor (BMS-536924; Selleck). Lysates were probed with the indicated antisera to assess IGF-1R autophosphorylation and phosphorylation of Akt.

     

     

    PLoS One 2010 5, e11729 . BMS-536924 purchased from Selleck.

    Inhibition of IGF-1R signaling upregulates the PGC-1α mRNA levels in myoblast. (C),The effects of BMS-536924 on the IGF-II-stimulated Akt and Erk phosphorylation. C2C12 myoblasts were washed with SFM and incubated with IMC-A12 or BMS-526924 (1 μM) in DMEM containing 0.5% horse serum for 60 min, and incubated with IGF-II for 10 min. Cell lysates were collected and analyzed by western immunoblotting using specific antibodies. The relative gray density of pAKT/AKT (pERK/ERK) was listed underneath each line. The first lane was arbitrarily set as 1. D, Time course of BMS-536924 (1 μM) effects on the PGC-1α levels. The expression of PGC-1α mRNA was measured by qRT-PCR and was normalized to cyclophilin mRNA.

    Mol Cell Biochem, 2017, 432(1-2):199-208. BMS-536924 purchased from Selleck.

  • Clin Cancer Res, 2018, doi:10.1158/1078-0432.CCR-17-37255. BMS-536924 purchased from Selleck.

Purity & Quality Control

Choose Selective IGF-1R Inhibitors

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
Insulin Receptor [1] IGF-1R [1]
()
FAK [1] MEK [1] LCK [1]
73 nM 100 nM 150 nM 182 nM 341 nM
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]

Protocol

Kinase Assay:

[2]

+ Expand

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 Research:

[3]

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  • 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.


    (Only for Reference)
Animal Research:

[4]

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  • Animal Models: TGBC-1TKB cells are subcutaneously injected into nude mice.
  • Formulation: BMS-536924 is dissolved in a mixture of polyethylene glycol 400 (PEG400/water, 4:1 vol/vol).
  • Dosages: 70 mg/kg
  • Administration: Oral once daily for 2 weeks
    (Only for Reference)

Solubility (25°C)

In vitro DMSO 96 mg/mL (200.01 mM)
Water Insoluble
Ethanol Insoluble
In vivo Add solvents to the product individually and in order(Data is from Selleck tests instead of citations):
30% PEG400+0.5% Tween80+5% propylene glycol
For best results, use promptly after mixing.
30 mg/mL

* Please note that Selleck tests the solubility of all compounds in-house, and the actual solubility may differ slightly from published values. This is normal and is due to slight batch-to-batch variations.

Chemical Information

Molecular Weight 479.96
Formula

C25H26ClN5O3

CAS No. 468740-43-4
Storage powder
in solvent
Synonyms HY-10262, CS-0117

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Tech Support

Answers to questions you may have can be found in the inhibitor handling instructions. Topics include how to prepare stock solutions, how to store inhibitors, and issues that need special attention for cell-based assays and animal experiments.

Handling Instructions

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Frequently Asked Questions

  • Question 1:

    What are the differences between S1012 ans S1034?

  • Answer:

    The most remarkable difference between these two IGF-IR inhibitors is S1012 BMS-536924 is a ATP-competitive inhibitor. You will get more information differences between IR inhibitors in this reference: http://www.sciencedirect.com/science/article/pii/S1359644605035129.

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Cell Lines Assay Type Concentration Incubation Time Formulation Activity Description PMID