Dual IGF-1R/InsR Inhibitor BMS-754807 is an oral small molecule inhibitor of insulin-like growth factor 1 receptor (IGF-1R) and insulin receptor (InsR) tyrosine kinases with potential antineoplastic activity.

MET:5.6 nM, TrkB:4.1 nM, Insulin receptor:1.7 nM, TrkA:7.4 nM, IGF-1R:1.8 nM

MS-754807（6.25 mg/kg）在转基因衍生的IGF-Sal肿瘤小鼠模型中实现完全的肿瘤生长抑制,同时抑制相关的pIGF-1R和pAKT.在具有IGF-1R-Sal肿瘤的裸鼠中,BMS-754807（12.5 mg/kg,口服）抑制肿瘤和血清中的IGF-1R磷酸化.25 mg/kg BMS-754807作用于携带KT-5 (Wilms),KT-14 (rhabdoid),Rh28 (rhabdomyosarcoma)和 OS-1移植瘤的小鼠模型,对肿瘤有明显抑制作用.BMS-754807作用于一组选定的上皮(IGF-1R-Sal,GEO和Colo205）,造血（JJN3）和间质（RD1和Rh41）移植瘤模型,抑制肿瘤生长,肿瘤生长抑制率从53％至115％不等.

BMS-754807以13 nM,6 nM和21 nM的IC 50抑制IGF-1R-Sal细胞,Rh41和Geo中的IGF-1R的磷酸化。BMS-754807抑制IGF-1R-Sal细胞,Rh41和Geo中Akt的磷酸化,IC5??0为22 nM,13 nM和16 nM。BMS-754807诱导Rh41细胞凋亡。BMS-754807作用于IGF-Sal 细胞系,抑制IGF-1R (IC50 = 13 nM),下游靶点Akt (IC50 = 22 nM) 和MAPK(IC50 = 13 nM) 的磷酸化。在儿科临床前期试验计划（PPTP）中,BMS-754807作用于23种细胞系,平均EC50值为0.62 μM。包括间叶细胞（尤因氏,横纹肌肉瘤,成神经细胞瘤和脂肪肉瘤）,上皮细胞（乳腺癌,肺癌,胰腺癌,结肠癌和胃癌）和造血干细胞（多发性骨髓瘤和白血病）,IC50值从5 nM 到 365 nM。BMS-754807 抑制 IGF-1R-Sal细胞和RH41细胞增殖,IC50分别为7 nM 和5 nM。

Kinase inhibition assays: The primary screen for BMS-754807 is an in vitro kinase assay using recombinant human IGF-1 receptor enzyme in biochemical assays using synthetic peptide KKSRGDYMTMQIG as a phosphoacceptor substrate. The selectivity profile is evaluated against multiple recombinant enzymes that are generated at BMS or purchased externally. The enzymatic assays are performed in Ubottom 384-well plates using a 30 μL reaction volume in assay buffer (100 mM Hepes pH 7.4, 10 mM MgCl2, 0.015% Brij35 and 4 mM DTT). The 60 minute reactions are initiated by combining ATP (concentration equivalent to Km ATP), 1.5 μM fluoresceinlabeled peptide substrate, enzyme and BMS-754807. The reactions are terminated with EDTA. The reaction mixtures are analyzed on the Caliper LabChip 3000 by electrophoretic separation of the fluorescent substrate and phosphorylated product. Inhibition data are calculated by comparison to enzyme-free control reactions for 100% inhibition and vehicle-only reactions for 0% inhibition. Compounds are dissolved in dimethylsulfoxide (DMSO, 10 mM stock) and evaluated at eleven concentrations. IC50 values are derived by non-linear regression analysis of the dose response curves.

Cells are grown at their optimal density in RPMI +GlutaMax supplemented with 10% heat-inactivated fetal bovine serum (FBS), 10 mM Hepes, penicillin, and streptomycin. Cell proliferation is evaluated by incorporation of 3H-thymidine into DNA after exposure of cells to BMS-754807 for 72 hours. Results are expressed as an IC50, which is the drug concentration required to inhibit cell proliferation by 50% compared with untreated control cells.(Only for Reference)