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.

MS-754807 (6.25 mg/kg) achieved complete tumor growth inhibition in a transgenic-derived IGF-Sal tumor model in mice, while simultaneously inhibiting associated pIGF-1R and pAKT. In nude mice with IGF-1R-Sal tumors, BMS-754807 (12.5 mg/kg, orally) inhibited tumor and serum IGF-1R phosphorylation. At a dose of 25 mg/kg, BMS-754807 significantly inhibited tumor growth in mouse models carrying KT-5 (Wilms), KT-14 (rhabdoid), Rh28 (rhabdomyosarcoma), and OS-1 xenografts. Furthermore, BMS-754807 effectively suppressed tumor growth across a selection of epithelial (IGF-1R-Sal, GEO, and Colo205), hematopoietic (JJN3), and mesenchymal (RD1 and Rh41) xenograft models, with tumor growth inhibition rates ranging from 53% to 115%.

BMS-754807 inhibits the phosphorylation of IGF-1R in IGF-1R-Sal cells, Rh41, and Geo with IC50 values of 13 nM, 6 nM, and 21 nM, respectively. It similarly inhibits the phosphorylation of Akt in these cells, with IC50 values of 22 nM, 13 nM, and 16 nM. Additionally, BMS-754807 induces apoptosis in Rh41 cells and suppresses the proliferation of IGF-1R-Sal and Rh41 cells, with IC50 values of 7 nM and 5 nM, respectively. In the pediatric preclinical testing program (PPTP), BMS-754807 exhibited activity across 23 cell lines with an average EC50 value of 0.62 μM, covering a range of cell types including mesenchymal (Ewing's, rhabdomyosarcoma, neuroblastoma, and liposarcoma), epithelial (breast, lung, pancreatic, colon, and gastric cancers), and hematopoietic stem cells (multiple myeloma and leukemia), with IC50 values spanning from 5 nM to 365 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)