BMS-536924 is a potent small molecule dual IGF-IR/IR kinase inhibitor, which shows antitumor activity in multiple tumor models. BMS-536924 inhibits cellular proliferation and disrupts Akt and MAPK phosphorylation. BMS-536924 also inhibits FAK and Lck with IC50 of 150 nM and 341 nM, respectively. BMS-536924 induced a dose-dependent inhibition of proliferation, with an accumulation of cells in G(0)/G(1,), and completely blocked CD8-IGF-IR-induced migration, invasion, and anchorage-independent growth in monolayer culture. In vitro, BMS-536924 inhibited leukemic colony formation in CD34+ clinical AML samples.
|Cell lines||TGBC-1TKB, TGBC-2TKB and TGBC-14TKB cell lines|
|Preparation method||In vitro cell growth.
Four thousand cells were seeded into a 96-well plate and each was treated with several concentrations of BMS-536924. Cell growth was measured using WST-1 reagent (Roche, Basel, Switzerland), as described previously.
|Concentrations||0, 1, 5, 10μM|
|Incubation time||0, 1, 2, 3, 4 days|
|Animal models||TGBC-1TKB tumour xenograft in nude mice|
|Formulation||a mixture of polyethylene glycol 400 (PEG400 ⁄ water, 4:1 vol ⁄ vol)|
|Dosages||70 mg ⁄ kg once daily for 2 weeks|
|Body Surface Area (m2)||0.007||0.025||0.15||0.05||0.02||0.5|
|Animal A (mg/kg) = Animal B (mg/kg) multiplied by||Animal B Km|
|Animal A Km|
For example, to modify the dose of resveratrol used for a mouse (22.4 mg/kg) to a dose based on the BSA for a rat, multiply 22.4 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for resveratrol of 11.2 mg/kg.
|Source||Onco Targets Ther (2015). Figure 1. BMS-536924|
|Method||cell viability assay|
|Cell Lines||TMZ-resistant cells|
|Incubation Time||24, 48, or 72 h|
|Results||BMS-536924 also significantly reduced the viability of both TMZ-sensitive and -resistant lines, in a time-dependent manner|
Insulin-like growth factor receptor expression is associated with aggressive phenotypes and has therapeutic activity in biliary tract cancers.
Ohashi H, et al. Cancer Sci. 2012 Feb;103(2):252-61. PMID: 22044563.
Expression of insulin receptor isoform A and insulin-like growth factor-1 receptor in human acute myelogenous leukemia: effect of the dual-receptor inhibitor BMS-536924 in vitro.
Wahner Hendrickson AE, et al. Cancer Res. 2009 Oct 1;69(19):7635-43. PMID: 19789352.
BMS-536924 reverses IGF-IR-induced transformation of mammary epithelial cells and causes growth inhibition and polarization of MCF7 cells.
Litzenburger BC, et al. Clin Cancer Res. 2009 Jan 1;15(1):226-37. PMID: 19118050.
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AXL1717 (picropodophyllin, Picropodophyllotoxin, PPP) is a non-competitive, potent, and specific inhibitor of IGF-1Rα/β with IC50 of 1 nM.
BMS-754807 is an ATP-competitive dual-kinase inhibitor of IGF-1R and IR with IC50s of 1.8 nM and 1.7 nM, respectively.
PQ401 is an insulin growth factor-1 receptor (IGF-1R) inhibitor.
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