product name BMS-754807
Description: BMS-754807 is a potent, orally bioavailable and reversible inhibitor of IGF-1R/InsR with IC50 of 1.8 nM/1.7 nM in cell-free assays, it is less potent to Met, Aurora A/B, TrkA/B and Ron, and shows little activity to Flt3, Lck, MK2, PKA, PKC etc. IGF-1R antagonist BMS-7548077 binds to IGF-1R, preventing IGF-1 ligand binding and activation of IGF-1R-mediated signaling pathways, inhibition of IGF-1R-mediated signaling pathways may result in the inhibition of tumor cell proliferation and the induction of tumor cell apoptosis.
References: Mol Cancer Ther. 2009 Dec;8(12):3341-9; J Med Chem. 2009 Dec 10;52(23):7360-3.
461.49
Formula
C23H24FN9O
CAS No.
1001350-96-4
Storage
-20℃ for 3 years in powder form
-80℃ for 2 years in solvent
Solubility (In vitro)
DMSO: 92 mg/mL (199.4 mM)
Water: <1 mg/mL
Ethanol: 92 mg/mL (199.4 mM)
Solubility (In vivo)
2% DMSO+30% PEG 300+ddH2O: 5 mg/mL
Synonyms
other peoduct :References PubMed ID：:http://www.ncbi.nlm.nih.gov/pubmed/19402914
| In Vitro |
In vitro activity: BMS-754807 effectively inhibits the growth of a broad range of human tumor cell lines of different histologic origins including mesenchymal (Ewings, rhabdomyosarcoma, neuroblastoma, and liposarcoma), epithelial (breast, lung, pancreatic, colon, and gastric), and hematopoietic (multiple myeloma and leukemia), the IC50 values range from 5 nM to 365 nM for the most sensitive cell lines. BMS-754807 inhibits proliferation of IGF-1R-Sal cells and RH41 cells with IC50 of 7 nM and 5 nM. BMS-754807 inhibits phosphorylation of IGF-1R in IGF-1R-Sal cells, Rh41 and Geo with IC50 of 13 nM, 6 nM and 21 nM. BMS-754807 inhibits phosphorylation of Akt in IGF-1R-Sal cells, Rh41 and Geo with IC50 of 22 nM, 13 nM and 16 nM. BMS-754807 induces greater apoptosis in Rh41 cells by 24 hours as indicated by an increased sub-G1 peak (23.1%), compared with control (2.4%). BMS-754807 inhibits the phosphorylation of IGF-1R (IC50 = 13nM) and the downstream targets Akt (IC50 = 22nM) and MAPK (IC50 = 13nM) in the IGF-Sal cell line with IC50 consistent with the antiproliferative IC50 (7 nM) in this cell line. The crystal structure of BMS-754807 cocrystallized with the kinase domain of IGF-1R shows that the donor/acceptor/donor hydrogen bond triad with Met1052 and Glu1050 within the hinge region of the kinase. BMS-754807 shows a median EC50 value of 0.62 μM against 23 cell lines in the pediatric preclinical testing program (PPTP). Kinase Assay: 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, 10mM stock) and evaluated at eleven concentrations. IC50 values are derived by non-linear regression analysis of the dose response curves. Cell Assay: Cells (IGF-1R-Sal, RH41 and Geo cell lines) 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. |
|---|---|
| In Vivo | BMS-754807 (12.5mg/kg, orally) inhibits IGF-1R phosphorylation in tumor and serum in IGF-1R-Sal tumor–bearing nude mice. BMS-754807 inhibits 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%. BMS-754807 (6.25 mg/kg) achieves complete tumor growth inhibition in the transgenic-derived IGF-Sal tumor mouse model with correlated inhibition of pIGF-1R and pAKT. The protein binding for BMS-754807 ranges from of 98.5% in mouse plasma to 95.9% in human plasma. BMS-754807 results in clearance of 113 (mL/min)/kg, 20 (mL/min)/kg, 3.5 (mL/min)/kg and 41 (mL/min)/kg. BMS-754807 (25 mg/kg) significantly inhibits tumor in KT-5 (Wilms), KT-14 (rhabdoid), Rh28 (rhabdomyosarcoma), and OS-1 xenografts mice model. |
| Animal model | Nude mice bearing IGF-1R-Sal, GEO, Colo205, JJN3, RD1 or Rh41 tumor |
| Formulation & Dosage | Dissolved in mixture of polyethylene glycol 400 (PEG400/water (4:1; vol/vol); 150mg/kg; p.o. |
| References | Mol Cancer Ther. 2009 Dec;8(12):3341-9; J Med Chem. 2009 Dec 10;52(23):7360-3. |
Related Posts
product name BMS-754807
Description: BMS-754807 is a potent, orally bioavailable and reversible inhibitor of IGF-1R/InsR with IC50 of 1.8 nM/1.7 nM in cell-free assays, it is less potent to Met, Aurora A/B, TrkA/B and Ron, and shows little activity to Flt3, Lck, MK2, PKA, PKC etc. IGF-1R antagonist BMS-7548077 binds to IGF-1R, preventing IGF-1 ligand binding and activation of IGF-1R-mediated signaling pathways, inhibition of IGF-1R-mediated signaling pathways may result in the inhibition of tumor cell proliferation and the induction of tumor cell apoptosis.
References: Mol Cancer Ther. 2009 Dec;8(12):3341-9; J Med Chem. 2009 Dec 10;52(23):7360-3.
461.49
Formula
C23H24FN9O
CAS No.
1001350-96-4
Storage
-20℃ for 3 years in powder form
-80℃ for 2 years in solvent
Solubility (In vitro)
DMSO: 92 mg/mL (199.4 mM)
Water: <1 mg/mL
Ethanol: 92 mg/mL (199.4 mM)
Solubility (In vivo)
2% DMSO+30% PEG 300+ddH2O: 5 mg/mL
Synonyms
other peoduct :References PubMed ID：:http://www.ncbi.nlm.nih.gov/pubmed/19402914
| In Vitro |
In vitro activity: BMS-754807 effectively inhibits the growth of a broad range of human tumor cell lines of different histologic origins including mesenchymal (Ewings, rhabdomyosarcoma, neuroblastoma, and liposarcoma), epithelial (breast, lung, pancreatic, colon, and gastric), and hematopoietic (multiple myeloma and leukemia), the IC50 values range from 5 nM to 365 nM for the most sensitive cell lines. BMS-754807 inhibits proliferation of IGF-1R-Sal cells and RH41 cells with IC50 of 7 nM and 5 nM. BMS-754807 inhibits phosphorylation of IGF-1R in IGF-1R-Sal cells, Rh41 and Geo with IC50 of 13 nM, 6 nM and 21 nM. BMS-754807 inhibits phosphorylation of Akt in IGF-1R-Sal cells, Rh41 and Geo with IC50 of 22 nM, 13 nM and 16 nM. BMS-754807 induces greater apoptosis in Rh41 cells by 24 hours as indicated by an increased sub-G1 peak (23.1%), compared with control (2.4%). BMS-754807 inhibits the phosphorylation of IGF-1R (IC50 = 13nM) and the downstream targets Akt (IC50 = 22nM) and MAPK (IC50 = 13nM) in the IGF-Sal cell line with IC50 consistent with the antiproliferative IC50 (7 nM) in this cell line. The crystal structure of BMS-754807 cocrystallized with the kinase domain of IGF-1R shows that the donor/acceptor/donor hydrogen bond triad with Met1052 and Glu1050 within the hinge region of the kinase. BMS-754807 shows a median EC50 value of 0.62 μM against 23 cell lines in the pediatric preclinical testing program (PPTP). Kinase Assay: 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, 10mM stock) and evaluated at eleven concentrations. IC50 values are derived by non-linear regression analysis of the dose response curves. Cell Assay: Cells (IGF-1R-Sal, RH41 and Geo cell lines) 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. |
|---|---|
| In Vivo | BMS-754807 (12.5mg/kg, orally) inhibits IGF-1R phosphorylation in tumor and serum in IGF-1R-Sal tumor–bearing nude mice. BMS-754807 inhibits 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%. BMS-754807 (6.25 mg/kg) achieves complete tumor growth inhibition in the transgenic-derived IGF-Sal tumor mouse model with correlated inhibition of pIGF-1R and pAKT. The protein binding for BMS-754807 ranges from of 98.5% in mouse plasma to 95.9% in human plasma. BMS-754807 results in clearance of 113 (mL/min)/kg, 20 (mL/min)/kg, 3.5 (mL/min)/kg and 41 (mL/min)/kg. BMS-754807 (25 mg/kg) significantly inhibits tumor in KT-5 (Wilms), KT-14 (rhabdoid), Rh28 (rhabdomyosarcoma), and OS-1 xenografts mice model. |
| Animal model | Nude mice bearing IGF-1R-Sal, GEO, Colo205, JJN3, RD1 or Rh41 tumor |
| Formulation & Dosage | Dissolved in mixture of polyethylene glycol 400 (PEG400/water (4:1; vol/vol); 150mg/kg; p.o. |
| References | Mol Cancer Ther. 2009 Dec;8(12):3341-9; J Med Chem. 2009 Dec 10;52(23):7360-3. |