Background
BMS-754807 is a potent and small molecular inhibitor which targets the IGF-1R/IR family kinases with Ki <2 nmol/L[1]. The efficacy of BMS-754807 on normal tissues and tumor cell cycle is believed to be different from the effects of continuous inhibition by anti-IGF-1R antibodies.[2]
BMS-754807 could effectively inhibit the growth of many human tumor types from in vitro perspective, such as mesenchymal, hematopoietic and epithelial tumor cell lines with an IC50 value of 5–365 nmol/L. It can also induce sub-G1 fraction accumulation and an increase in poly ADP ribose polymerase and Caspase 3 cleavage, suggesting that it can lead to apoptosis in a human rhabdomyosarcoma cell line (Rh41). Furthermore, as a pyrrolotriazine and reversible ATP-competitive antagonist of IGF-1R, BMS-754807 was shown to inhibit the catalytic domain of the IGF-1R, and proved to inhibit the IGF-1R and IR activity by using the in-vitro kinase assays. Since the antibodies can bind to IGF-1R but not to IR, this could be regardere as an escape mechanism for IGF-II and insulin signaling.[3]
参考文献:
[1] Q.S. Chu，S.W. Kim，P.M. Ellis，L. Mileshkin，R.H. de Boer，J.S. Park，T. Pellas，F. Huang，F. Graf Finckenstein，A. Dhar. BMS-754807, an oral dual IGF-1R/insulin receptor (IR) inhibitor: initial results from a Phase 1 dose- and schedule-?nding study in combination with carboplatin/paclitaxel in subjects with solid tumors. European Journal of Cancer Supplements. November 2010, 8(7): 131.
[2] Vattoly J. Majo, Victoria Arango, Norman R. Simpson, Jaya Prabhakaran, Suham A. Kassir, Mark D. Underwood, Mihran Bakalian, Peter Canoll, J. John Mann, J.S. Dileep Kumar. Synthesis and in vitro evaluation of [18F]BMS-754807: A potential PET ligand for IGF-1R. Bioorganic & Medicinal Chemistry Letters. July 2013, 23(14): 4191-4194.
[3] Joan M. Carboni, Mark Wittman, Zheng Yang, et al.. BMS-754807, a small molecule inhibitor of insulin-like growth factor-1R/IR. Mol Cancer Ther. 2009;8:3341-3349.
Protocol
| Cell experiment: [1] |
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Cell lines
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IGF-1R-Sal, Rh41 and Geo cells
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Preparation method
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The solubility of this compound in DMSO is >10 mM. General tips for obtaining a higher concentration: Please warm the tube at 37 °C for 10 minutes and/or shake it in the ultrasonic bath for a while.Stock solution can be stored below -20°C for several months.
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Reaction Conditions
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1 μM, (72 hours for cell proliferation inhibition; 1 hour for phosphorylation inhibition
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Applications
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Cell proliferation was evaluated by incorporation of 3H-thymidine into DNA after exposure of cells to BMS-754807 with concentrations from 0.1 to 1000 nM. BMS-754807 inhibited cell proliferation with IC50 values of 7, 5 and 365 nM for IGF-1R-Sal, Rh41 and Geo cells, respectively. The IC50 values for inhibition of the pIGF-1R by BMS-754807 and downstream components (e.g., pAkt) were very similar. In contrast, there was greater inhibition against pMAPK in IGF-1R-Sal cells compared with Rh41 and Geo, indicating that additional compensatory pathways such as EGFR might be important in driving signals in both Rh41 and Geo cell types.
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| Animal experiment : [1] |
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Animal models
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Nude mice bearing various tumor xenografts (Sal-IGF, GEO, Colo205, JJN3, Rh41 or RD1)
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Dosage form
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Oral administration, 0.01 mL/g of body weight
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Applications
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BMS-754807 inhibited tumor growth in a selected group of epithelial (IGF-1R-Sal, GEO and Colo205), hematopoietic (JJN3) and mesenchymal (RD1 and Rh41) xenograft tumor models with TGI ranging from 53% to 115%. In the highly sensitive Rh41 rhabdomyosarcoma, BMS-754807 was effective at a dose level of 3.125 mg/kg twice daily and as low as 6.25 mg/kg once daily.
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Other notes
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Please test the solubility of all compounds indoor, and the actual solubility may slightly differ with the theoretical value. This is caused by an experimental system error and it is normal.
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参考文献:
[1] Carboni J M, Wittman M, Yang Z, et al. BMS-754807, a small molecule inhibitor of insulin-like growth factor-1R/IR. Molecular Cancer Therapeutics, 2009, 8(12): 3341-3349.
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