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Purity: ≥98%
BMS-777607 (also called as BMS817378; ASLAN002) is an orally bioavailable inhibitor of the tyrosine kinase c-Met with potential antitumor activity. It exhibits 40-fold higher selectivity for inhibiting Met over Lck, VEGFR-2, and TrkA/B. In cell-free assays, it inhibits c-Met, Axl, Ron, and Tyro3 with IC50s of 3.9 nM, 1.1 nM, 1.8 nM, and 4.3 nM.
| Targets |
c-Met (IC50 = 3.9 nM); Axl (IC50 = 1.1 nM); Ron (IC50 = 1.8 nM); Tyro3 (IC50 = 4.3 nM)
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| ln Vitro |
BMS-777607 is an ATP-competitive, selective Met kinase inhibitor that exhibits selective inhibition of proliferation in Met-driven tumor cell lines, including GTL-16 cell line, H1993, and U87. It also potently blocks the autophosphorylation of c-Met with an IC50 of 20 nM in GTL-16 cell lysates.[1] In PC-3 and DU145 prostate cancer cells, BMS-777607 inhibits c-Met autophosphorylation triggered by hepatocyte growth factor (HGF) with an IC50 of less than 1 nM. While BMS 777607 shows little effect on tumor cell growth, it does show almost complete inhibition at 0.5 μM on HGF-induced cell scattering in PC-3 and DU145 cells. In both cell lines, BMS 777607 also inhibits stimulated cell migration and invasion in a dose-dependent manner (IC50 < 0.1 μM).[2] BMS 777607 (~10 μM) applied for two hours to highly metastatic murine KHT cells potently eliminates basal levels of autophosphorylated c-Met with an IC50 of 10 nM without affecting the total amount of c-Met. This results in a dose-dependent inhibition of downstream signaling molecules such as Akt, p70S6K, S6, ERK, and others through phosphorylation. Applied at doses in the nanomolar range, which includes MET gene knockdown, BMS-777607 (~1 μM) treatment for 24 hours significantly suppresses KHT cell motility, invasion, and scatter while having a minimal impact on colony formation and cell proliferation.[3]
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| ln Vivo |
BMS 777607 (6.25–50 mg/kg) given orally to athymic mice dramatically reduces the tumor volumes of GTL-16 human tumor xenografts without causing any apparent toxicity.[1] When injected with rodent fibrosarcoma KHT cells into 6-to 8-week-old female C3H/HeJ mice, BMS 777607 (25 mg/kg/day) significantly reduces the number of KHT lung tumor nodules (28.3%), improves the morphological hemorrhage, and significantly reduces the metastatic phenotype without apparent systemic toxicity when compared to the control treatment. In comparison to the vehicle control, a low dose of BMS 777607 (10 mg/kg) also provides a slight but insignificant inhibition of lung nodule formation.[3]
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| Enzyme Assay |
The kinase reaction comprises 30 μL of kinase buffer (20 mM Tris-Cl, 5 mM MnCl2, 0.1 mg/mL BSA, 0.5 mM DTT), 3 μg of poly(Glu/Tyr), 0.12 μCi 33P γ-ATP, and 1 μM ATP expressed by the baculovirus. Cold trichloroacetic acid (TCA), added to a final concentration of 8%, ends the reaction after an hour of incubation at 30 °C. A Filtermate universal harvester is used to gather TCA precipitates onto GF/C unifilter plates, and a TopCount 96-well liquid scintillation counter is used to quantify the filters. To find the concentration needed to prevent 50% of substrate phosphorylation, dose response curves are created (IC50). In duplicate, BMS 777607 is dissolved at a concentration of 10 mM in dimethylsulfoxide (DMSO) and assessed at ten concentrations.
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| Cell Assay |
The MTT assay and trypan blue exclusion are used to determine the proliferation and death of KHT cells after they are subjected to serial dilution of BMS 777607 for 96 hours. The BMS 777607 is added to KHT cell colonies, and after a 24-hour incubation period, the colonies are stained with crystal violet (0.1%) and captured on camera to measure the scattering of the cells. A sterile 1-milliliter pipette tip is used to make a 2-millimeter incision on the confluent KHT cell monolayer. The cell monolayer is then treated with BMS-777607 for a full day. To assess cell migration, the number of cells that have moved into the denuded area is counted on four adjacent fields at random. Commercial transwell inserts (8 μm pore membrane) pre-loaded with Matrigel are incubated with serum-free medium at 37 °C for two hours to allow Matrigel to rehydrate, whether or not BMS 777607 is present. This allows for the examination of cell invasion. Subsequently, cells suspended in serum-free medium are inserted into the upper chamber (5 × 103/insert), while the lower chamber is utilized as a chemoattractant for complete medium containing 10% FBS. The Matrigel is taken off and the inserts are stained with crystal violet after a 24-hour incubation period. The invaded cells on the filter's underside are counted and photographed.
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| Animal Protocol |
Male Balb/C mice are used to study the pharmacokinetics of BMS 777607. After an overnight fast, two groups of animals (N = 6 per group; 20–25 g) receive BMS 777607 either by gavage (10 mg/kg) or as an intravenous (IV) bolus dose (5 mg/kg) through the tail vein. Six hours after the dose, the mice are fed. Retro-orbital bleeding is used to collect blood samples (about 0.2 mL) at 0.05 (or 0.25 for oral), 0.5, 1, 3, 6, 8, and 24 hours after the dose. A composite pharmacokinetic profile is produced by blenching half of the animals in each group at 0.05 (or 0.25 for oral), 1, 6, and 24 hours, and the other half at 0.5, 3, and 8 hours (3 mice per time point). Serum is obtained by allowing blood samples to coagulate and centrifuging them at 4°C (1500–2000 ×g). Before being analyzed by LC/MS/MS, serum samples are kept at about 20°C.
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| References | |
| Additional Infomation |
N-[4-[(2-amino-3-chloro-4-pyridinyl)oxy]-3-fluorophenyl]-4-ethoxy-1-(4-fluorophenyl)-2-oxo-3-pyridinecarboxamide is an aromatic amide.
BMS-777607 has been investigated for the basic science of Malignant Solid Tumour. MET Tyrosine Kinase Inhibitor BMS-777607 is an inhibitor of MET tyrosine kinase with potential antineoplastic activity. MET tyrosine kinase inhibitor BMS-777607 binds to c-Met protein, or hepatocyte growth factor receptor (HGFR), preventing binding of hepatocyte growth factor (HGF) and disrupting the MET signaling pathway; this agent may induce cell death in tumor cells expressing c-Met. c-Met, a receptor tyrosine kinase overexpressed or mutated in many tumor cell types, plays an important role in tumor cell proliferation, survival, invasion, and metastasis, and in tumor angiogenesis. |
| Molecular Formula |
C25H19CLF2N4O4
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|---|---|
| Molecular Weight |
512.89
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| Exact Mass |
512.106
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| Elemental Analysis |
C, 58.54; H, 3.73; Cl, 6.91; F, 7.41; N, 10.92; O, 12.48
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| CAS # |
1025720-94-8
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| Related CAS # |
1025720-94-8; 1196681-44-3 (deleted);
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| PubChem CID |
24794418
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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 |
667.9±55.0 °C at 760 mmHg
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| Flash Point |
357.7±31.5 °C
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| Vapour Pressure |
0.0±2.0 mmHg at 25°C
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| Index of Refraction |
1.672
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| LogP |
4.86
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| Hydrogen Bond Donor Count |
2
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| Hydrogen Bond Acceptor Count |
8
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| Rotatable Bond Count |
7
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| Heavy Atom Count |
36
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| Complexity |
867
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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(C([H])=C([H])N(C2C([H])=C([H])C(=C([H])C=2[H])F)C1=O)OC([H])([H])C([H])([H])[H])=O
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| InChi Key |
VNBRGSXVFBYQNN-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C25H19ClF2N4O4/c1-2-35-19-10-12-32(16-6-3-14(27)4-7-16)25(34)21(19)24(33)31-15-5-8-18(17(28)13-15)36-20-9-11-30-23(29)22(20)26/h3-13H,2H2,1H3,(H2,29,30)(H,31,33)
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| Chemical Name |
N-[4-(2-amino-3-chloropyridin-4-yl)oxy-3-fluorophenyl]-4-ethoxy-1-(4-fluorophenyl)-2-oxopyridine-3-carboxamide
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| Synonyms |
ASLAN 002; BMS 817378; BMS 777607; ASLAN-002; ASLAN002; BMS-817378; BMS817378; BMS-777607; BMS777607; ASLAN-002; N-(4-(2-Amino-3-chloropyridin-4-yloxy)-3-fluorophenyl)-4-ethoxy-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide; ASLAN002;
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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 |
| 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 (4.87 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 (4.87 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in 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 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. View More
Solubility in Formulation 3: ≥ 2.5 mg/mL (4.87 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. Solubility in Formulation 4: 4% DMSO+30% PEG 300+ddH2O: 5 mg/mL |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.9497 mL | 9.7487 mL | 19.4974 mL | |
| 5 mM | 0.3899 mL | 1.9497 mL | 3.8995 mL | |
| 10 mM | 0.1950 mL | 0.9749 mL | 1.9497 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.
| NCT Number | Recruitment | interventions | Conditions | Sponsor/Collaborators | Start Date | Phases |
| NCT00605618 | Completed | Drug: BMS-777607 | Advanced Solid Tumors | Bristol-Myers Squibb | October 2012 | Phase 1 |
| NCT01721148 | Completed | Drug: ASLAN002 (BMS 777607) |
Malignant Solid Tumour | ASLAN Pharmaceuticals | October 2012 | Phase 1 |
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BMS-777607 blocks the HGF-stimulated c-Met signaling pathways. Mol Cancer Ther. 2010 Jun;9(6):1554-61. |
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