BMS-754807 is a potent and reversible inhibitor of the type-1 insulin-like growth factor receptor family kinases (Ki, <2 nmol/L). BMS-754807 effectively inhibits the growth of a broad range of human tumor types in vitro, including mesenchymal, epithelial and hematopoietic tumor cell lines (IC50, 5-365 nmol/L). In vitro, BMS-754807 showed a median EC(50) value of 0.62 μM against the PPTP cell lines. BMS-754807 caused apoptosis in a human rhabdomyosarcoma cell line, Rh41, as shown by an accumulation of the sub-G1 fraction, as well as by an increase in poly ADP ribose polymerase and Caspase 3 cleavage. BMS-754807 is active in vivo in multiple xenograft tumor models with tumor growth inhibition ranging from 53% to 115% and at a minimum effective dose of as low as 6.25 mg/kg dosed orally daily. BMS-754807 is currently in phase I development for the treatment of a variety of human cancers.
|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||Int J Mol Sci (2017). Figure 5. BMS-754807|
|Method||IGF1R/IR and AR antagonists|
|Cell Lines||TNBC cell|
|Incubation Time||48 h|
|Results||In this panel of TNBC cell lines, inhibition by BMS-754807 consistently induced cell death. These data suggest that inhibitors targeting IGF1R/IR homo- or heterodimers can prevent TNBC tumor growth.|
Dual IGF-1R/InsR inhibitor BMS-754807 synergizes with hormonal agents in treatment of estrogen-dependent breast cancer.
Hou X, et al. Cancer Res. 2011 Dec 15;71(24):7597-607. PMID: 22042792.
Initial testing (stage 1) of the IGF-1 receptor inhibitor BMS-754807 by the pediatric preclinical testing program.
Kolb EA, et al. Pediatr Blood Cancer. 2011 Apr;56(4):595-603. PMID: 21298745.
Differential mechanisms of acquired resistance to insulin-like growth factor-i receptor antibody therapy or to a small-molecule inhibitor, BMS-754807, in a human rhabdomyosarcoma model.
Huang F, et al. Cancer Res. 2010 Sep 15;70(18):7221-31. PMID: 20807811.
BMS-754807, a small molecule inhibitor of insulin-like growth factor-1R/IR.
Carboni JM, et al. Mol Cancer Ther. 2009 Dec;8(12):3341-9. PMID: 19996272.
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