AMG 337 is a potent and highly selective small molecule
ATP-competitive MET kinase inhibitor that demonstrates robust activity in
MET-dependent cancer models. In enzymatic assays, AMG 337 inhibited MET kinase
activity with an IC50 less than 5 nM. AMG 337 demonstrated exquisite
selectivity for MET when profiled against a diverse panel of over 400 protein and
lipid kinases in a competitive binding assay. In cellular assays, AMG 337
inhibited HGF-dependent MET phosphorylation with an IC50 of less
than 10 nM [1].
AMG 337 was profiled in cell viability assays
using a diverse panel of over 200 cancer cell lines where on treatment with AMG
337 affected the viability of only two gastric cancer cell lines (SNU-5 and
Hs746T), both of which harbor amplification of the MET gene. The AMG 337 IC50
in the two sensitive cell lines was less than 50 nM, and greater than 10 µM in
all other tested cell lines.
Common Name: AMG-337
Synonyms: AMG337; AMG 337; AMG-337
IUPAC Name: -
CAS Number: -
SMILES: -
Mechanism of Action: Kinase Inhibitor; MET Kinase Inhibitor
Indication: Various Cancers; Anti-Tumor Therapy
Development Stage: Phase II
Company: Amgen Inc
The receptor tyrosine kinase c-Met and its natural ligand,
hepatocyte growth factor (HGF), are involved in cell proliferation, migration,
and invasion and are essential for normal embryonic development. Deregulation
of c-Met/HGF signaling can lead to tumorigenesis and metastasis and has been
implicated in a variety of cancers. Several mechanisms lead to deregulation,
including overexpression of c-Met and/or HGF, amplification of the MET gene, or
activating mutations of c-Met, all of which have been found in human cancers.
AMG 337 is a potent and highly selective inhibitor of wild-type
and some mutant forms of MET. In a competitive binding assay conducted on 402
human kinases, AMG 337 bound only to MET. In a cell viability study, the only
cell lines that responded to an AMG 337 analog were gastric cancer cells
harboring MET gene amplification. None of the other cell lines were sensitive
to the AMG 337 analog and none harbored MET gene amplification. In secondary
pharmacology assays with transporters, enzymes, ion channels, and receptors,
binding to the adenosine transporter was the only activity inhibited.
In vivo, oral administration of AMG 337 resulted
in robust dose-dependent anti-tumor efficacy in MET amplified gastric cancer
xenograft models, with inhibition of tumor growth consistent with the
pharmacodynamic modulation of MET signaling. Further studies in an expanded
panel of additional cancer cell lines derived from gastric, NSCLC, and
esophageal cancer confirmed that the in-vitro anti-proliferative activity of
AMG 337 correlated with amplification of MET. In those cell lines, treatment
with AMG 337 inhibited downstream PI3K and MAPK signaling pathways, which
translated into growth arrest as evidenced by an accumulation of cells in the
G1 phase of the cell cycle, a concomitant reduction in DNA synthesis, and the
induction of apoptosis [1].
1. Hughes, P. E.; et. al. Abstract 728: AMG 337, a novel, potent and selective MET kinase inhibitor, has robust growth inhibitory activity in MET-dependent cancer models. Cancer Res 2014, 74, 728.
2. Boezio, A. A.; et. al. Discovery and optimization of potent and selective triazolopyridazine series of c-Met inhibitors. Bioorg Med Chem Lett 2009, 19(22), 6307-6312.
3. ClinicalTrials.gov Phase 2 Study of AMG 337 in MET Amplified Gastric/Esophageal Adenocarcinoma or Other Solid Tumors. NCT02016534 (retrieved 10-06-2015)
4. ClinicalTrials.gov A Study of AMG 337 in Subjects With Advanced Solid Tumors. NCT01253707 (retrieved 10-06-2015)
In a small subset of patients with MET-amplified
gastrointestinal (GI) tumors, monotherapy with the investigational agent AMG
337 produced a "dramatic" response. Of the 13 patients with
MET-amplified gastric and esophageal cancers, eight experienced a response. The
overall response rate in this group of patients was 62%. Response was rapid,
with time to response being 4 weeks in most cases. Patients achieved tumor
shrinkage and symptomatic improvement. One patient achieved a complete response
and is still on treatment at 155 weeks; the others achieved partial responses
or stable disease. This has led to further trials, including Phase II trials MET
amplified gastric/esophageal adenocarcinoma or other solid tumors.
Structure of AMG 337
Till date Amgen has not disclosed the structure
for AMG 337. Taking clue for AMG 208, and publications in various articles, one
of the possible candidates for AMG 337 can be:
The profile of the molecule matches to those of
the Amgen has released for AMG 337. The inhibition of kinase activity (IC50
= 5 nM) and inhibition of HGF-mediated c-Met phosphorylation in PC3 cells (IC50
= 3 nM) are reported [2].
One another possible structure for AMG-337 as suggested by few others is:
One another possible structure for AMG-337 as suggested by few others is:
It is claimed to be released by Amgen but it is not confirmed. Moreover, no citation is provided. Need to look into it as well.
1. Hughes, P. E.; et. al. Abstract 728: AMG 337, a novel, potent and selective MET kinase inhibitor, has robust growth inhibitory activity in MET-dependent cancer models. Cancer Res 2014, 74, 728.
2. Boezio, A. A.; et. al. Discovery and optimization of potent and selective triazolopyridazine series of c-Met inhibitors. Bioorg Med Chem Lett 2009, 19(22), 6307-6312.
3. ClinicalTrials.gov Phase 2 Study of AMG 337 in MET Amplified Gastric/Esophageal Adenocarcinoma or Other Solid Tumors. NCT02016534 (retrieved 10-06-2015)
4. ClinicalTrials.gov A Study of AMG 337 in Subjects With Advanced Solid Tumors. NCT01253707 (retrieved 10-06-2015)
