Antibodies
BMS-754807
- 貨號 Cat. No.
- S1124
- 規格 Size
- 5~200mg
- 品牌 Brand
- Selleckchem
Description
BMS-754807
Catalog No.S1124
BMS-754807 is a potent and reversible inhibitor of IGF-1R/InsR with IC50 of 1.8 nM/1.7 nM, less potent to Met, Aurora A/B, TrkA/B and Ron, and shows little activity to Flt3, Lck, MK2, PKA, PKC etc. Phase 1/2.
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Distributor Tel: +886-2-2827-1197jimmy@new.abscience.com.tw
Biological Activity
| Description | BMS-754807 is a potent and reversible inhibitor of IGF-1R/InsR with IC50 of 1.8 nM/1.7 nM, less potent to Met, Aurora A/B, TrkA/B and Ron, and shows little activity to Flt3, Lck, MK2, PKA, PKC etc. Phase 1/2. | |||||
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| Targets | IGF-1R | IR | Met | TrkA | TrkB | |
| IC50 | 1.8 nM | 1.7 nM | 5.6 nM | 7.4 nM | 4.1 nM [1] | |
| In vitro | BMS-754807 effectively inhibits the growth of a broad range of human tumor cell lines of different histologic origins including mesenchymal (Ewing’s, 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%). [1]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.[2] BMS-754807 shows a median EC50 value of 0.62 μM against 23 cell lines in the pediatric preclinical testing program (PPTP). [3] | |||||
| 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%. [1] 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. [2] BMS-754807 (25 mg/kg) significantly inhibits tumor in KT-5 (Wilms), KT-14 (rhabdoid), Rh28 (rhabdomyosarcoma), and OS-1 xenografts mice model. [3] | |||||
| Features | Muti-inhibitor of the IGR-1R/IR family. | |||||
Protocol(Only for Reference)
Kinase Assay: [1]
| 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, 10mM stock) and evaluated at eleven concentrations. IC50 values are derived by non-linear regression analysis of the dose response curves. |
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Cell Assay: [1]
| Cell lines | IGF-1R-Sal, RH41 and Geo cell lines |
|---|---|
| Concentrations | 365 nM |
| Incubation Time | 72 hours |
| Method | 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. |
Animal Study: [1]
| Animal Models | IGF-1R-Sal, GEO, Colo205, JJN3, RD1 or Rh41 tumor–bearing nude mice |
|---|---|
| Dosages | 150 mg/kg |
| Administration | Orally |
| Solubility | 30% PEG400/0.5% Tween80/5% propylene glycol, 20 mg/mL |
References
Clinical Trial Information( data from http://clinicaltrials.gov)
| NCT Number | Recruitment | Conditions | Sponsor /Collaborators | Start Date | Phases |
|---|---|---|---|---|---|
| NCT00908024 | Active, not recruiting | Colorectal Cancer|Head and Neck Cancer|Neoplasm Metastasis | Bristol-Myers Squibb | 2007-11 | Phase 1|Phase 2 |
| NCT00788333 | Completed | Breast Cancer | Bristol-Myers Squibb | 2009-07 | Phase 1|Phase 2 |
| NCT00898716 | Completed | Neoplasms | Bristol-Myers Squibb | 2009-09 | Phase 1 |
| NCT01225172 | Active, not recruiting | Breast Cancer | Bristol-Myers Squibb | 2011-06 | Phase 2 |
| NCT01525823 | Completed | Healthy Volunteers | Bristol-Myers Squibb | 2012-02 | Phase 1 |
Chemical Information
| Molecular Weight (MW) | 461.49 |
|---|---|
| Formula | C23H24FN9O |
| CAS No. | 1001350-96-4 |
| Storage | 3 years -20℃Powder |
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| 6 months-80℃in DMSO | |
| Syonnyms | N/A |
| Solubility (25°C) * | In vitro | DMSO | 92 mg/mL (199 mM) |
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| Water | <1 mg/mL (<1 mM) | ||
| Ethanol | 92 mg/mL (199 mM) | ||
| In vivo | 30% PEG400/0.5% Tween80/5% propylene glycol, | 20 mg/mL | |
| * <1 mg/ml means slightly soluble or insoluble. * Please note that Selleck tests the solubility of all compounds in-house, and the actual solubility may differ slightly from published values. This is normal and is due to slight batch-to-batch variations. | |||
| Chemical Name | (S)-1-(4-(5-cyclopropyl-1H-pyrazol-3-ylamino)pyrrolo[1,2-f][1,2,4]triazin-2-yl)-N-(6-fluoropyridin-3-yl)-2-methylpyrrolidine-2-carboxamide |
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