Synonym
AMG337; AMG-337; AMG 337.
IUPAC/Chemical Name
(R)-6-(1-(8-fluoro-6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)ethyl)-3-(2-methoxyethoxy)-1,6-naphthyridin-5(6H)-one
InChi Key
DWHXUGDWKAIASB-CQSZACIVSA-N
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
SMILES Code
O=C1C2=C(N=CC(OCCOC)=C2)C=CN1[C@@H](C3=NN=C4C(F)=CC(C5=CN(C)N=C5)=CN43)C
Purity
>98% (or refer to the Certificate of Analysis)
Shipping Condition
Shipped under ambient temperature as non-hazardous chemical. This product is stable enough for a few weeks during ordinary shipping and time spent in Customs.
Storage Condition
Dry, dark and at 0 - 4 C for short term (days to weeks) or -20 C for long term (months to years).
Solubility
Soluble in DMSO, not in water
Shelf Life
>2 years if stored properly
Drug Formulation
This drug may be formulated in DMSO
Stock Solution Storage
0 - 4 C for short term (days to weeks), or -20 C for long term (months).
HS Tariff Code
2934.99.9001
Biological target:
AMG-337 is a potent and highly selective small molecule ATP-competitive MET kinase inhibitor with an IC50 of < 5nM in enzymatic assays.
In vitro activity:
The effect of AMG 337 on cell proliferation was examined in a panel of 22 cancer cell lines that were reported to have elevated MET gene copy number, only 2 of which, SNU-5 and Hs746T, overlapped with the larger 260 cell line panel profiled with Compound 5 (Supplementary Table S2; ref. 27). Growth conditions for each cell line were optimized and cell viability was assessed following 72 hours of treatment with AMG 337. In addition, array CGH analysis was performed to quantify and confirm MET gene copy number, and cell lysates were generated to measure levels of total and phosphorylated MET protein. Nine cell lines exhibited sensitivity to AMG 337, (IC50 < 50 nmol/L; Fig. 1B and C), whereas the remaining cell lines were insensitive (IC50 > 3 μmol/L). A strong correlation was observed between high-level focal amplification of MET [aCGH log2 ratio of >2.5 (copy number >12), amplicon size <q-arm chromosome 7] and sensitivity to AMG 337, with seven of eight focally amplified cell lines demonstrating sensitivity to AMG 337 (Fig. 1C). The lack of sensitivity to AMG 337 in the remaining focally amplified cell line, NCI-H1573 (Fig. 1D), was presumably driven by a downstream activating mutation in KRAS (G12A) that promoted MAPK and PI3K signaling in the presence of MET inhibition (Supplementary Fig. S3).
Reference: Mol Cancer Ther. 2016 Jul;15(7):1568-79. http://mct.aacrjournals.org/cgi/pmidlookup?view=long&pmid=27196782
In vivo activity:
Daily oral administration was used to evaluate the in vivo antitumor activity of AMG 337 in two patient-derived xenograft (PDX) models of hepatocellular carcinoma (LI0612 and LI1078). AMG 337 exerted potent antiproliferative activity against 2 of 40 hepatocellular carcinoma cell lines, namely, MHCC97H (IC50, 0.015 μmol/L) and HCCLM3 (IC50, 0.025 μmol/L). Both sensitive cell lines showed MET amplification (MET/CEN-7 >2.0) assessed by FISH, and high MET expression (3+ IHC) assessed by IHC. AMG 337 potently inhibited p-MET in all cell lines with detectable levels of total MET. However, the dose-dependent inhibition of downstream effectors of HGF/MET signaling, including p-GAB1, p-AKT, and p-ERK, was limited to those cell lines sensitive to AMG 337 in a viability assay (MHCC97H and HCCLM3). AMG 337 significantly inhibited tumor growth at all doses tested in the MET-amplified and MET-high-expressing hepatocellular carcinoma PDX model LI0612 and had no effect on tumor growth in the non-MET-amplified and MET-low-expressing hepatocellular carcinoma PDX model LI1078.
Reference: Mol Cancer Ther. 2016 Jun;15(6):1227-37. http://mct.aacrjournals.org/cgi/pmidlookup?view=long&pmid=27196749
|
Solvent |
mg/mL |
mM |
| Solubility |
| DMSO |
50.0 |
107.88 |
| Ethanol |
50.0 |
107.88 |
Note: There can be variations in solubility for the same chemical from different vendors or different batches from the same vendor. The following factors can affect the solubility of the same chemical: solvent used for crystallization, residual solvent content, polymorphism, salt versus free form, degree of hydration, solvent temperature. Please use the solubility data as a reference only. Warming and sonication will facilitate dissolving. Still have questions? Please contact our Technical Support scientists.
Preparing Stock Solutions
The following data is based on the
product
molecular weight
463.47
Batch specific molecular weights may vary
from batch to batch
due to the degree of hydration, which will
affect the solvent
volumes required to prepare stock solutions.
| Concentration / Solvent Volume / Mass |
1 mg |
5 mg |
10 mg |
| 1 mM |
1.15 mL |
5.76 mL |
11.51 mL |
| 5 mM |
0.23 mL |
1.15 mL |
2.3 mL |
| 10 mM |
0.12 mL |
0.58 mL |
1.15 mL |
| 50 mM |
0.02 mL |
0.12 mL |
0.23 mL |
In vitro protocol:
1. Hughes PE, Rex K, Caenepeel S, Yang Y, Zhang Y, Broome MA, Kha HT, Burgess TL, Amore B, Kaplan-Lefko PJ, Moriguchi J, Werner J, Damore MA, Baker D, Choquette DM, Harmange JC, Radinsky R, Kendall R, Dussault I, Coxon A. In Vitro and In Vivo Activity of AMG 337, a Potent and Selective MET Kinase Inhibitor, in MET-Dependent Cancer Models. Mol Cancer Ther. 2016 Jul;15(7):1568-79. doi: 10.1158/1535-7163.MCT-15-0871. Epub 2016 Apr 19. PMID: 27196782.
2. Du Z, Caenepeel S, Shen Y, Rex K, Zhang Y, He Y, Tang ET, Wang O, Zhong W, Zhou H, Huang J, Huang E, Hu L, Coxon A, Zhang M. Preclinical Evaluation of AMG 337, a Highly Selective Small Molecule MET Inhibitor, in Hepatocellular Carcinoma. Mol Cancer Ther. 2016 Jun;15(6):1227-37. doi: 10.1158/1535-7163.MCT-15-0745. Epub 2016 Mar 29. PMID: 27196749.
In vivo protocol:
1. Du Z, Caenepeel S, Shen Y, Rex K, Zhang Y, He Y, Tang ET, Wang O, Zhong W, Zhou H, Huang J, Huang E, Hu L, Coxon A, Zhang M. Preclinical Evaluation of AMG 337, a Highly Selective Small Molecule MET Inhibitor, in Hepatocellular Carcinoma. Mol Cancer Ther. 2016 Jun;15(6):1227-37. doi: 10.1158/1535-7163.MCT-15-0745. Epub 2016 Mar 29. PMID: 27196749.
2. Hughes PE, Rex K, Caenepeel S, Yang Y, Zhang Y, Broome MA, Kha HT, Burgess TL, Amore B, Kaplan-Lefko PJ, Moriguchi J, Werner J, Damore MA, Baker D, Choquette DM, Harmange JC, Radinsky R, Kendall R, Dussault I, Coxon A. In Vitro and In Vivo Activity of AMG 337, a Potent and Selective MET Kinase Inhibitor, in MET-Dependent Cancer Models. Mol Cancer Ther. 2016 Jul;15(7):1568-79. doi: 10.1158/1535-7163.MCT-15-0871. Epub 2016 Apr 19. PMID: 27196782.
1: Lee J, Tran P, Klempner SJ. Targeting the MET Pathway in Gastric and
Oesophageal Cancers: Refining the Optimal Approach. Clin Oncol (R Coll Radiol).
2016 Feb 12. pii: S0936-6555(16)00035-2. doi: 10.1016/j.clon.2016.01.009. [Epub
ahead of print] PubMed PMID: 26880063.
2: Boezio AA, Copeland KW, Rex K, K Albrecht B, Bauer D, Bellon SF, Boezio C,
Broome MA, Choquette D, Coxon A, Dussault I, Hirai S, Lewis R, Lin MJ, Lohman J,
Liu J, Peterson EA, Potashman M, Shimanovich R, Teffera Y, Whittington DA, Vaida
KR, Harmange JC. Discovery of
(R)-6-(1-(8-Fluoro-6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-y
l)ethyl)-3-(2-methoxyethoxy)-1,6-naphthyridin-5(6H)-one (AMG 337), a Potent and
Selective Inhibitor of MET with High Unbound Target Coverage and Robust In Vivo
Antitumor Activity. J Med Chem. 2016 Feb 11. [Epub ahead of print] PubMed PMID:
26812066.
3: Aprile G, Leone F, Giampieri R, Casagrande M, Marino D, Faloppi L, Cascinu S,
Fasola G, Scartozzi M. Tracking the 2015 Gastrointestinal Cancers Symposium:
bridging cancer biology to clinical gastrointestinal oncology. Onco Targets Ther.
2015 May 22;8:1149-56. doi: 10.2147/OTT.S82624. eCollection 2015. Review. PubMed
PMID: 26045669; PubMed Central PMCID: PMC4447178.
