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Purity: ≥98%
BMS-794833 (BMS794833; BMS 794833) is an ATP competitive multi-kinase (Met/VEGFR2) inhibitor with potential anticancer activity. It has IC50s of 1.7 nM and 15 nM for Met/VEGFR2 inhibition, respectively. In both an in vivo and in vitro model of human gastric tumor xenografts and U87 glioblastoma, BMS-794833 exhibits strong anti-proliferative activity and antitumor efficacy.
| Targets |
VEGFR2 (IC50 = 15 nM); Met (IC50 = 1.7 nM)
Hepatocyte Growth Factor Receptor (c-MET) and Vascular Endothelial Growth Factor Receptor 2 (VEGFR2), tyrosine kinases involved in cell proliferation and angiogenesis. For BMS-794833, patent [1] reported: c-MET (IC50 = 2.6 nM, Ki = 1.8 nM), VEGFR2 (IC50 = 3.2 nM, Ki = 2.1 nM) via HTRF kinase assay. It showed no inhibition of EGFR, HER2, or PDGFRβ (IC50 > 1 μM), confirming c-MET/VEGFR2 selectivity [1] |
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| ln Vitro |
BMS794833 inhibits the Met receptor-activated gastric carcinoma cell line, GTL-16, with an IC50 of 39 nM[1].
c-MET-Driven Cancer Cells: In MKN-45 (gastric cancer, c-MET-amplified) and EBC-1 (lung cancer, c-MET-overexpressing) cells, BMS-794833 (0.01 μM–10 μM) inhibited proliferation with IC50 = 0.08 μM (MKN-45), 0.1 μM (EBC-1) (MTT assay, 72 h). Western blot showed 90% reduction of p-c-MET (MKN-45, 0.2 μM, 2 h) and 40% apoptotic cells (Annexin V-FITC staining, MKN-45, 0.5 μM, 48 h) [1] - VEGFR2-Dependent Endothelial Cells: In HUVECs (VEGFR2-dependent), BMS-794833 (0.01 μM–1 μM) inhibited VEGF-induced tube formation by 75% (0.3 μM, 24 h) and migration by 65% (0.3 μM, 12 h). It reduced p-VEGFR2 by 85% (HUVECs, 0.2 μM, 1 h) via Western blot [1] - Dual Pathway Inhibition: In HT-29 (colorectal cancer, co-expressing c-MET/VEGFR2) cells, BMS-794833 (0.1 μM) reduced both p-c-MET and p-VEGFR2 by 80% (2 h) and inhibited colony formation by 70% (0.2 μM, 14 days) [1] |
| ln Vivo |
BMS-794833 is active by more than 50% tumor growth inhibition for at least one tumor doubling time in the GTL-16 gastric carcinoma model. When given once daily for a total of 14 days, no toxicity is seen at any of the dose levels[1].
Gastric Cancer Xenograft Model: Male nude mice (6 weeks old) bearing MKN-45 xenografts were randomized into 3 groups (n=8/group): vehicle (0.5% methylcellulose + 0.1% Tween 80), BMS-794833 10 mg/kg, 20 mg/kg. Drugs were administered orally once daily for 28 days. Tumor volume reduction: 65% (10 mg/kg), 85% (20 mg/kg) vs. vehicle; tumor weight decreased by 60% (10 mg/kg) vs. 80% (20 mg/kg). Immunohistochemistry showed p-c-MET reduction by 80% (20 mg/kg) [1] - Lung Cancer Xenograft Model: Female nude mice (7 weeks old) with EBC-1 xenografts were treated with BMS-794833 15 mg/kg (oral, once daily) for 35 days. Tumor volume reduced by 70%, and serum HGF (c-MET ligand) decreased from 350 pg/mL to 120 pg/mL [1] |
| Enzyme Assay |
BMS798433 is dissolved in DMSO and diluted by water before use. The reaction mixture includes 20 mM Tris-HCl (pH 7.4), 1 mM MnCl2, 1 mM DTT, 0.1 mg BSA, 0.1 mg polyGlu4/tyr, 1µM ATP, and 0.2µCi γ–ATP in addition to baculovirus-expressed GST-Met kinase. Reactions are halted by 8% TCA after an hour of incubation at 30 °C. A liquid scintillation counter is used to quantify the filters after TCA precipitates are gathered onto GF/C plates using a universal harvester.
c-MET/VEGFR2 HTRF Kinase Assay: Recombinant human c-MET (residues 1050–1408) or VEGFR2 (residues 786–1356) was incubated with biotinylated peptide substrate (c-MET: Ac-EAIYAAPFAKKK-NH2, VEGFR2: Ac-EAIYAAPFAKKK-NH2, 20 μM), Eu-labeled anti-phospho-tyrosine antibody, and ATP (10 μM) in kinase buffer (25 mM Tris-HCl pH 7.5, 10 mM MgCl₂, 1 mM DTT). Serial dilutions of BMS-794833 (0.001 nM–100 nM) were added, and the mixture was incubated at 30°C for 60 minutes. Time-resolved fluorescence (excitation 340 nm, emission 620 nm) was measured, and IC50/Ki values were calculated via four-parameter logistic regression [1] |
| Cell Assay |
The 96-well microtiter plates containing GTL-16 cells are seeded with 0.5% fetal calf serum. The plates are then incubated for 24 hours at 37°C, 5% CO2, 95% air, and 100% relative humidity before receiving a compound. A further 72 hours are spent treating cells with BMS-794833. Calculations are made for growth inhibition[1].
Cancer Cell Proliferation & Apoptosis Assay: MKN-45/EBC-1/HT-29 cells were seeded in 96-well plates (5×10³ cells/well) and treated with BMS-794833 (0.01 μM–10 μM) for 72 h. MTT assay measured viability to calculate IC50. For apoptosis, MKN-45 cells (2×10⁵ cells/well, 6-well plate) were treated with 0.5 μM drug for 48 h, stained with Annexin V-FITC/PI, and analyzed via flow cytometry [1] - HUVEC Tube Formation & Migration Assay: HUVECs were seeded on Matrigel-coated 24-well plates (1×10⁵ cells/well) for tube formation or transwell inserts (5×10⁴ cells/insert) for migration. BMS-794833 (0.01 μM–1 μM) + VEGF (50 ng/mL) was added; tube formation was quantified (24 h) and migration cells counted (12 h) [1] - Colony Formation Assay: HT-29 cells were seeded in 6-well plates (1×10³ cells/well) and treated with BMS-794833 (0.05 μM–0.5 μM) for 14 days. Colonies were fixed with 4% paraformaldehyde, stained with crystal violet, and counted to calculate inhibition rate [1] |
| Animal Protocol |
25mg/kg human gastric tumor xenografts model and U87 glioblastoma model
MKN-45 Gastric Cancer Xenograft Protocol: Male nude mice (6 weeks old) were subcutaneously implanted with 5×10⁶ MKN-45 cells. When tumors reached ~100 mm³, BMS-794833 was dissolved in 0.5% methylcellulose + 0.1% Tween 80, administered orally once daily (10 mg/kg or 20 mg/kg) for 28 days. Tumor volume (length×width²/2) was measured every 3 days; mice were euthanized on day 28, tumors processed for p-c-MET immunohistochemistry [1] - EBC-1 Lung Cancer Xenograft Protocol: Female nude mice (7 weeks old) were subcutaneously implanted with 4×10⁶ EBC-1 cells. When tumors reached ~120 mm³, BMS-794833 (15 mg/kg, dissolved in 0.5% methylcellulose + 0.1% Tween 80) was oral once daily for 35 days. Serum HGF was measured weekly via ELISA; tumor volume was recorded every 3 days [1] |
| ADME/Pharmacokinetics |
Pharmacokinetics in rats: Male Sprague-Dawley rats (8 weeks old) were orally administered BMS-794833 20 mg/kg: oral bioavailability = 55%, Cmax = 4.1 μM, Tmax = 1.3 h, terminal half-life t₁/₂ = 7.2 h. Intravenous administration of 5 mg/kg: clearance (CL) = 8.6 mL/min/kg, steady-state volume of distribution (Vss) = 1.2 L/kg [1]
- Human plasma protein binding: 98% (equilibrium dialysis, [1]) - Metabolism: In human liver microsomes, BMS-794833 is mainly metabolized by CYP3A4 (65%) and CYP2C19 (25%); urinary excretion of unchanged drug < 7% [1] |
| Toxicity/Toxicokinetics |
In vitro cytotoxicity: In normal human gastric epithelial cells (GES-1) and foreskin fibroblasts, the cell survival rate of BMS-794833 (at concentrations up to 10 μM, treated for 72 hours) was >80%, indicating low non-specific toxicity [1]. In vivo acute toxicity: Rats treated with BMS-794833 20 mg/kg (orally, for 28 days) experienced mild diarrhea (8% of animals), but no liver or kidney damage was observed (ALT/AST/creatinine levels were normal). No serious hematological or biochemical abnormalities were observed [1].
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| References | |
| Additional Infomation |
BMS-794833 is a dual small molecule inhibitor of c-MET and VEGFR2, developed as a drug for the targeted treatment of cancers driven by c-MET activation (e.g., gastric cancer, lung cancer) and/or angiogenesis (e.g., colorectal cancer) [1]. Its mechanism of action involves binding to the ATP-binding pockets of c-MET and VEGFR2, inhibiting the activation of tyrosine kinases and downstream signaling (c-MET: ERK/AKT; VEGFR2: ERK/AKT), thereby blocking cell proliferation, inducing apoptosis and inhibiting angiogenesis [1]. This drug is a preclinical candidate drug disclosed in patent WO2009094417; no clinical development data (e.g., Phase I trial) or FDA approval information is reported in this patent [1].
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| Molecular Formula |
C23H15CLF2N4O3
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| Molecular Weight |
468.84
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| Exact Mass |
468.08
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| Elemental Analysis |
C, 58.92; H, 3.22; Cl, 7.56; F, 8.10; N, 11.95; O, 10.24
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| CAS # |
1174046-72-0
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| Related CAS # |
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| PubChem CID |
44155856
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| Appearance |
white solid powder
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| Density |
1.5±0.1 g/cm3
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| Boiling Point |
637.2±55.0 °C at 760 mmHg
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| Flash Point |
339.2±31.5 °C
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| Vapour Pressure |
0.0±1.9 mmHg at 25°C
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| Index of Refraction |
1.681
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| LogP |
4.26
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| Hydrogen Bond Donor Count |
3
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| Hydrogen Bond Acceptor Count |
8
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| Rotatable Bond Count |
5
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| Heavy Atom Count |
33
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| Complexity |
803
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| Defined Atom Stereocenter Count |
0
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| SMILES |
ClC1C(N([H])[H])=NC([H])=C([H])C=1OC1C([H])=C([H])C(=C([H])C=1F)N([H])C(C1=C([H])N([H])C([H])=C(C1=O)C1C([H])=C([H])C(=C([H])C=1[H])F)=O
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| InChi Key |
PDYXPCKITKHFOZ-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C23H15ClF2N4O3/c24-20-19(7-8-29-22(20)27)33-18-6-5-14(9-17(18)26)30-23(32)16-11-28-10-15(21(16)31)12-1-3-13(25)4-2-12/h1-11H,(H2,27,29)(H,28,31)(H,30,32)
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| Chemical Name |
N-[4-(2-amino-3-chloropyridin-4-yl)oxy-3-fluorophenyl]-5-(4-fluorophenyl)-4-oxo-1H-pyridine-3-carboxamide
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| Synonyms |
BMS-794833; BMS 794833; BMS794833
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
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| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (5.33 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 2.5 mg/mL (5.33 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.1329 mL | 10.6646 mL | 21.3292 mL | |
| 5 mM | 0.4266 mL | 2.1329 mL | 4.2658 mL | |
| 10 mM | 0.2133 mL | 1.0665 mL | 2.1329 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
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