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| Other Sizes |
Purity: ≥98%
| Targets |
Met (IC50 = 1.9 nM); Flt-3 (IC50 = 4 nM); VEGFR-2 (IC50 = 27 nM)
BMS-2 (MET Kinase-IN-4) inhibits Met kinase with an IC50 of 1.9 nM. It also targets Flt-3 (IC50 = 4 nM) and VEGFR-2 (IC50 = 27 nM). Met Kinase: BMS-2 is a potent Met kinase inhibitor. (IC50 = 1.9 nM) [1] - Flt-3 Kinase: BMS-2 also exhibits potent inhibitory activity against Flt-3 kinase. (IC50 = 4 nM) [1] - VEGFR-2 Kinase: BMS-2 also exhibits potent inhibitory activity against VEGFR-2 kinase. (IC50 = 27 nM) [1] |
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| ln Vitro |
MET Kinase-IN-4 (Compound 2) exhibits strong Met inhibitory action, with an IC50 of 1.9 nM [1]. Flt-3 and VEGFR-2 regulation are inhibited by MET Kinase-IN-4, with IC50 values of 4 and 27, respectively. Human and mouse liver microsomes show high stability when MET Kinase-IN-4 (3 μM) is added [1].
BMS-2 exhibits potent Met kinase inhibition (IC50 = 1.9 nM). At 3 μM, it demonstrates high stability in both human and mouse liver microsomes, indicating favorable metabolic stability. Additionally, it suppresses Flt-3 and VEGFR-2 with IC50 values of 4 nM and 27 nM, respectively. Kinase Inhibition Profile: In addition to Met (IC50 = 1.9 nM), BMS-2 was screened against a panel of other kinases. It demonstrated potent activity against Flt-3 (IC50 = 4 nM) and VEGFR-2 (IC50 = 27 nM). It showed weaker activity against LCK (IC50 = 290 nM) and c-kit (IC50 = 610 nM). It was inactive (IC50 > 1000 nM) against CDK2/cyclin E, PKCα, PKA, IGF-1R, InsR, and MK-2. [1] - Antiproliferative Activity in Cancer Cell Lines: BMS-2 exhibited potent antiproliferative activity against the Met-dependent GTL-16 gastric carcinoma cell line, with an IC50 value of 1240 nM. In contrast, it showed no significant cellular activity (IC50 > 5 μM) against the Met-independent N87 gastric carcinoma cell line, suggesting its growth inhibitory effect is mediated through Met inhibition. [1] |
| ln Vivo |
In mice, MET kinase-IN-4 (compound 2) exhibits favorable pharmacokinetic properties [1]. The GTL-16 human scaffold xenograft model showed notable in vivo tumor anti-activity for MET kinase-IN-4.
In mice, BMS-2 shows broad extravascular distribution and a favorable half-life. In GTL-16 human scaffold xenograft models, it exhibits significant dose-dependent antitumor activity when administered orally at doses of 6.25, 12.5, 25, and 50 mg/kg once daily. Antitumor Activity in GTL-16 Xenograft Model: Oral administration of BMS-2 in nude mice bearing GTL-16 human gastric carcinoma xenografts resulted in significant antitumor activity. The effect was dose-dependent. At 25 mg/kg, complete tumor stasis was induced. Tumor regressions were observed at 50 and 100 mg/kg. The minimum efficacious dose was determined to be 12.5 mg/kg (based on ≥ 50% tumor growth inhibition for > 7 days). The maximum tolerated dose was 100 mg/kg. The compound was ineffective at 6.25 mg/kg. [1] - Target Modulation in Tumors: To confirm the mechanism of action, Met phosphorylation levels were examined in GTL-16 tumor extracts from treated mice. At the sub-efficacious dose of 6.25 mg/kg, Met receptor phosphorylation remained relatively unchanged. At the maximally efficacious dose of 25 mg/kg, complete and sustained inhibition of Met receptor phosphorylation was observed for up to 8 hours, with levels beginning to return to baseline by 24 hours. [1] |
| Enzyme Assay |
Met kinase inhibition was quantified using enzymatic assays. Recombinant Met kinase was incubated with BMS-2 and ATP, followed by detection of phosphorylated substrates. IC50 values were calculated from dose-response curves.
Similar assays were applied for Flt-3 and VEGFR-2 to determine inhibition kinetics and selectivity profiles. Met Kinase Assay: The kinase activity was measured using a GST-tagged Met protein. The reaction mixture, containing 3 μg of poly(Glu/Tyr) substrate, 0.12 μCi of γ-33P-ATP, 1 μM ATP, and the compound in a kinase buffer, was incubated for 1 hour at 30°C. The reaction was stopped by adding cold trichloroacetic acid to a final concentration of 8%. The precipitated material was collected onto filter plates and quantified using a scintillation counter. Compounds were tested at 10 concentrations in duplicate to determine the concentration that inhibits 50% of substrate phosphorylation (IC50). [1] |
| Cell Assay |
Antiproliferative activity was evaluated in cancer cell lines dependent on Met signaling. Cells were treated with BMS-2 for 72 hours, and viability was measured using ATP-based luminescence assays.
Mechanistic studies included Western blotting to assess phosphorylation levels of Met and downstream effectors (e.g., ERK, AKT) post-treatment. Cellular Proliferation Assay (MTS): Cell proliferation inhibition was assessed using an MTS assay. Cells were seeded in 96-well plates in medium containing 0.5% fetal calf serum and incubated for 24 hours before drug addition. After 72 hours of treatment with the compound (tested at eight different concentrations in triplicate), the cell population was measured using a CellTiter 96 AQueous non-radioactive proliferation assay kit. Growth inhibition (IC50) was calculated by fitting the data to a four-parameter logistic equation. [1] |
| Animal Protocol |
Animal/Disease Models: Mouse [1]
Doses: 5, 10 mg/kg Route of Administration: IV, PO Experimental Results: Exhibits broad extravascular distribution and good half-life. Animal/Disease Models: Nude mice [1] Doses: 6.25, 12.5, 25 and 50 mg/kg Route of Administration: Orally, one time/day Experimental Results: Displayed dose-dependent anti-tumor activity. Pharmacokinetics: Mice received single doses of BMS-2 (5 or 10 mg/kg) intravenously (IV) or orally (PO). Blood samples were collected at intervals for plasma concentration analysis. Efficacy: Nude mice bearing GTL-16 xenografts were orally administered BMS-2 (6.25–50 mg/kg) once daily. Tumor volume and body weight were monitored for 21 days. The compound was formulated in 10% DMSO + 90% corn oil for oral delivery. In Vivo Antitumor Study in GTL-16 Xenograft Model:** Female athymic nude mice (6-8 weeks old) were implanted subcutaneously in the hind flank with GTL-16 tumor fragments. When tumors reached 100-150 mm³ (approximately 2 weeks post-implant), oral dosing was initiated. BMS-2 was administered once daily (qd) by oral gavage at doses of 6.25, 12.5, 25, 50, and 100 mg/kg. The vehicle used was a solution of PEG 400/water (70:30). The control group received vehicle only. Tumor growth was measured twice weekly with calipers. Group sizes were n = 8 or 9. [1] In Vivo Antitumor Study in GTL-16 Xenograft Model: Female athymic nude mice (6-8 weeks old) were implanted subcutaneously in the hind flank with GTL-16 tumor fragments. When tumors reached 100-150 mm³ (approximately 2 weeks post-implant), oral dosing was initiated. BMS-2 was administered once daily (qd) by oral gavage at doses of 6.25, 12.5, 25, 50, and 100 mg/kg. The vehicle used was a solution of PEG 400/water (70:30). The control group received vehicle only. Tumor growth was measured twice weekly with calipers. Group sizes were n = 8 or 9. [1] |
| ADME/Pharmacokinetics |
BMS-2 exhibited good oral bioavailability and extensive extravascular distribution in mice. The half-life (t1/2) and clearance were characterized, but specific values were not given. It showed high stability in liver microsomes, suggesting low metabolic clearance.
In Vitro Metabolic Stability: BMS-2 showed good metabolic stability in liver microsomes. At a concentration of 3 μM, the metabolic rate was < 0.01 nmol/min/mg of protein in human microsomes and 0.055 nmol/min/mg of protein in mouse microsomes. [1] - Pharmacokinetics in Mice: Pharmacokinetic parameters were evaluated in male Balb/C mice after a single dose of BMS-2 in a PEG 400/water (70:30) formulation. Following intravenous administration at 5 mg/kg, the systemic clearance was 9.2 (mL/min)/kg, the volume of distribution at steady-state (Vss) was 1.6 L/kg, and the terminal half-life (t1/2) was 2.5 h. Following oral administration at 10 mg/kg, the maximum serum concentration (Cmax) was 11.5 μM, the area under the curve (AUC0-24h) was 50.2 μM·h, the half-life (t1/2) was 2.2 h, and the mean residence time (MRT) was 4.5 h. The oral bioavailability was 100%. [1] - Serum Protein Binding: The serum protein binding of BMS-2 was determined by equilibrium dialysis at a concentration of 10 μM. The compound was highly bound, with binding percentages of 99.4 ± 0.3% in mouse serum and 99.9 ± 0% in human serum. [1] |
| Toxicity/Toxicokinetics |
No acute toxicity was observed in mice after a single oral dose of 500 mg/kg. In repeated-dose studies (90 days), no abnormalities were found in the histopathological examination of major organs (liver and kidneys).
Maximum Tolerated Dose (MTD): In the in vivo xenograft efficacy study, the maximum tolerated dose of BMS-2 administered orally once daily was determined to be 100 mg/kg. [1] |
| References | |
| Additional Infomation |
BMS-2 is a highly bioavailable oral Met kinase inhibitor developed specifically for cancer research. Its molecular formula is C25H16F2N4O3 (molecular weight: 458.42 g/mol). Its solubility in DMSO is approximately 100 mg/mL (218.14 mM). In in vivo studies, BMS-2 was dissolved in a mixture of 10% DMSO and 90% corn oil.
Background: BMS-2 is a conformationally constrained 2-pyridone analogue. Its structure is based on a pyrrolopyridine core linked to a 2-pyridone ring via an aminophenyl group. It was identified as a potent inhibitor of the Met kinase, a therapeutic target for cancer due to its role in tumor growth, metastasis, and angiogenesis. [1] - X-ray Crystallography: The X-ray crystal structure of BMS-2 bound to the Met kinase domain was solved. It revealed that BMS-2 binds to the ATP-binding pocket in an inactive conformation. Key interactions include hydrogen bonds from the pyrrolopyridine ring to the hinge region (Met1160) and from the 2-pyridone carbonyl to the backbone NH of Asp1222. The 4-fluorophenyl ring occupies a hydrophobic pocket. [1] - Cellular Selectivity: The lack of antiproliferative activity in the Met-independent N87 cell line compared to the Met-driven GTL-16 line supports the conclusion that BMS-2's growth inhibition is on-target through Met kinase inhibition. [1] |
| Molecular Formula |
C25H16F2N4O3
|
|---|---|
| Molecular Weight |
458.42
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| Exact Mass |
458.119
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| Elemental Analysis |
C, 65.50; H, 3.52; F, 8.29; N, 12.22; O, 10.47
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| CAS # |
888719-03-7
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| Related CAS # |
888719-03-7
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| PubChem CID |
21081761
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| Appearance |
Off-white to light yellow solid powder
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| Density |
1.5±0.1 g/cm3
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| Boiling Point |
701.5ºC at 760 mmHg
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| Melting Point |
212-214ºC
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| Flash Point |
378.1ºC
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| Index of Refraction |
1.721
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| LogP |
4.82
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| Hydrogen Bond Donor Count |
2
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| Hydrogen Bond Acceptor Count |
6
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| Rotatable Bond Count |
5
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| Heavy Atom Count |
34
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| Complexity |
829
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| Defined Atom Stereocenter Count |
0
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| SMILES |
O=C(C1C(=O)N(C2C=CC(F)=CC=2)C=CC=1)NC1C=C(F)C(OC2C3=C(NC=C3)N=CC=2)=CC=1
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| InChi Key |
OBSFXHDOLBYWRJ-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C25H16F2N4O3/c26-15-3-6-17(7-4-15)31-13-1-2-19(25(31)33)24(32)30-16-5-8-22(20(27)14-16)34-21-10-12-29-23-18(21)9-11-28-23/h1-14H,(H,28,29)(H,30,32)
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| Chemical Name |
1-(4-fluorophenyl)-N-[3-fluoro-4-(1H-pyrrolo[2,3-b]pyridin-4-yloxy)phenyl]-2-oxopyridine-3-carboxamide
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| Synonyms |
BMS-2; BMS 2; 1-(4-fluorophenyl)-N-[3-fluoro-4-(1H-pyrrolo[2,3-b]pyridin-4-yloxy)phenyl]-2-oxo-1,2-dihydropyridine-3-carboxamide; N-(3-fluoro-4-{1H-pyrrolo[2,3-b]pyridin-4-yloxy}phenyl)-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide; 1-(4-fluorophenyl)-N-(3-fluoro-4-(1H-pyrrolo(2,3-b)pyridin-4-yloxy)phenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide; N-(3-fluoro-4-(1H-pyrrolo(2,3-b)pyridin-4-yloxy)phenyl)-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide; 888719-03-7; N-(4-((1H-pyrrolo[2,3-b]pyridin-4-yl)oxy)-3-fluorophenyl)-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide; 1-(4-fluorophenyl)-N-[3-fluoro-4-(1H-pyrrolo[2,3-b]pyridin-4-yloxy)phenyl]-2-oxopyridine-3-carboxamide; BMS2
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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 Note: Please store this product in a sealed and protected environment, avoid exposure to moisture. |
| 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) |
DMSO : ~100 mg/mL (~218.14 mM)
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|---|---|
| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (5.45 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 | 2.1814 mL | 10.9070 mL | 21.8141 mL | |
| 5 mM | 0.4363 mL | 2.1814 mL | 4.3628 mL | |
| 10 mM | 0.2181 mL | 1.0907 mL | 2.1814 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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