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Purity: ≥98%
AMG-337 is a novel, potent and highly selective small molecule ATP-competitive MET kinase inhibitor. In enzymatic assays, AMG 337 inhibited MET kinase activity with an IC50 of < 5nM nM. MET kinase activity was inhibited by AMG 337, with an IC50 of less than 5 nM nM. In a competitive binding assay, AMG 337 was profiled against a broad panel of over 400 protein and lipid kinases and showed remarkable selectivity for MET. AMG 337 inhibited HGF-dependent MET phosphorylation in cellular assays, showing an IC50 of less than 10 nM. AMG 337 was profiled in cell viability assays with a diverse panel of more than 200 cancer cell lines in order to find predictive genomic markers of response. Only two stomach cancer cell lines (SNU-5 and Hs746T), both of which have MET gene amplification, were impacted by treatment with AMG 337 in terms of viability. In all tested cell lines, the AMG 337 IC50 was > 10 μM, while it was < 50 nM in the two sensitive cell lines. In MET-amplified gastric cancer xenograft models, oral administration of AMG 337 produced a strong dose-dependent anti-tumor efficacy in vivo. This tumor growth inhibition was consistent with the pharmacodynamic modulation of MET signaling. To sum up, these results highlight the potential therapeutic use of AMG 337 as a treatment for tumors exhibiting dysregulated MET signaling, including MET amplification. AMG 337 is presently being studied in patients with solid tumors for safety, tolerability, and pharmacokinetics in a phase 1 clinical trial.
| Targets |
MET receptor (IC50 = 1 nM); MET(H1094R) (IC50 = 1 nM); MET(M1250T) (IC50 = 4.7 nM); MET(V1092I) (IC50 = 21.5 nM)
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| ln Vitro |
AMG 337 inhibits WT MET and a subset of MET mutants present in papillary renal cell carcinoma with a potent effect on their enzymatic activity. It is most likely due to a disruption of the inactive confirmation of the activation loop in the MET kinase domain that AMG 337 is unable to inhibit the Y1230 and D1228 mutants. Moreover, AMG 337 has an IC50 of 5 nM against PC3 cells, which inhibits HGF-induced MET phosphorylation in cells. In cancer cell lines that rely on MET, AMG 337 prevents cell division. In MET-amplified gastric cancer cell lines, AMG 337 inhibits signaling via the PI3K and MAPK pathways, which has a significant impact on cell survival and proliferation[1].
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| ln Vivo |
AMG 337 demonstrates remarkable effectiveness, as it inhibits Gab-1 phosphorylation by over 90% at a dosage of 0.75 mg/kg, or 32 nmol/L of free drug concentration. It is possible that AMG 337 possesses the preclinical qualities necessary to investigate the function of MET in human cancer because it is well tolerated when given at doses that correspond with total MET inhibition for a full day[1].
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| Cell Assay |
Cells are seeded in 96-well plates at an ideal density to guarantee proliferation throughout the course of the experiments in order to assess the impact of AMG 337 on viability. AMG 337 is diluted 10-fold, three times, serially, and applied to cells for 72 hours at a maximum concentration of 3 mmol/L. The CellTiter-Glo Luminescent Cell Viability Assay is used to quantify viability.
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| Animal Protocol |
Female CD1 nu/nu or athymic nude mice(Tumor xenograft models)
0.1, 0.5, 0.75, 1, 2, or 3 mg/kg by oral gavage |
| References |
| Molecular Formula |
C23H22FN7O3
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|---|---|
| Molecular Weight |
463.4643
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| Exact Mass |
463.473
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| Elemental Analysis |
C, 59.60; H, 4.78; F, 4.10; N, 21.16; O, 10.36
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| CAS # |
1173699-31-4
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| Related CAS # |
1173699-31-4
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| Appearance |
Solid powder
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| SMILES |
C[C@H](C1=NN=C2N1C=C(C=C2F)C3=CN(N=C3)C)N4C=CC5=C(C4=O)C=C(C=N5)OCCOC
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| InChi Key |
DWHXUGDWKAIASB-CQSZACIVSA-N
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| InChi Code |
InChI=1S/C23H22FN7O3/c1-14(30-5-4-20-18(23(30)32)9-17(11-25-20)34-7-6-33-3)21-27-28-22-19(24)8-15(13-31(21)22)16-10-26-29(2)12-16/h4-5,8-14H,6-7H2,1-3H3/t14-/m1/s1
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| Chemical Name |
6-[(1R)-1-[8-fluoro-6-(1-methylpyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl]ethyl]-3-(2-methoxyethoxy)-1,6-naphthyridin-5-one
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| Synonyms |
AMG337; AMG 337; AMG-337
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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) |
DMSO: 95~100 mg/mL (~205.0 mM)
Ethanol: ~95 mg/mL (~205.0 mM) |
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (5.39 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 (5.39 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 (5.39 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.1577 mL | 10.7884 mL | 21.5768 mL | |
| 5 mM | 0.4315 mL | 2.1577 mL | 4.3154 mL | |
| 10 mM | 0.2158 mL | 1.0788 mL | 2.1577 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 |
| NCT01253707 | Completed | Drug: AMG 337 | Cancer Oncology |
Amgen | December 8, 2010 | Phase 1 |
| NCT02096666 | Completed | Drug: AMG 337 | Stomach Neoplasms | Amgen | April 15, 2014 | Phase 1 Phase 2 |
| NCT02016534 | Terminated | Drug: AMG 337 | Stomach Neoplasms | Amgen | February 2014 | Phase 2 |
| NCT03132155 | Terminated | Drug: AMG 337 | Clear Cell Sarcoma | NantPharma, LLC | May 2, 2018 | Phase 2 |
 Expert Opin Ther Targets.2012 Jun;16(6):553-72. |
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