AMG 337

Protein target name:

MET

Mechanism of action:

InhibitorATP Competitive

Recommended Concentration for use in cells:

100 nM

Probe Information

Target and Probe Information

Target Details

Target class:

Protein kinase

Subclass:

HUGO ID:

HGNC:7029

Entrez gene ID:

4233

UNIPROT ID:

P08581

Target alias:

MET proto-oncogene receptor tyrosine kinase, AUTS9, DFNB97, HGFR, RCCP2, c-Met

Probe Details

Chemical Probes Portal ID:

CPP1195

Probe alias:

AMG337, AMG-337, cpd 23

PubChem CID:

112499967

SMILES string:

CC(C1=NN=C2N1C=C(C=C2F)C3=CN(N=C3)C)N4C=CC5=NC=C(C=C5C4=C)OCCOC

InChi Key:

WKIALOXOAZXGMG-UHFFFAOYSA-N

Orthogonal probe:

CapmatinibSGX-523MK-8033

Validation in Cells and Model Organisms

In vitro validation

On target activity

Potency:

IC50

1 nM WT

Potency assay:

TR-FRET

Structure-activity relationship:

yes

Off target activity

Probe Selectivity in Vitro:

competitive binding assays illustrated the selectivity of AMG 337, binding only MET when profiled against a diverse panel of 402 human kinases at 1 µM

In cell validation

On target activity in cells

Potency in cells:

IC50

5 nM

Potency assay (cells):

Quantitative electrochemiluminescence immunoassay, CellTiter-Glo Luminescent Cell Viability Assay.

Target engagement assay (cells):

CellTiter-Glo assay was used to evaluate the effect of AMG 337 on cell viability in a panel of cell lines.

In vivo validation

Organism:

MouseRat

Dose:

0.1-10 mg/Kg

Route of delivery:

OralIntravenous

Plasma half life:

3 h

Systemic clearance:

0.27 (IV), 1.6 (PO) L/h/Kg

Fraction of probe bound to plasma protein:

30 %

Primary Reference

Reference (doi):

10.1158/1535-7163.MCT-15-0871 10.1021/acs.jmedchem.5b01716

Reference (PMID):

27196782 26812066

Endorsed probe

The Chemical Probes Portal endorses this compound as chemical probe for use in cells and in model organisms.

SAB Rating

Rating for use in Cells

3 review(s)

Rating for use in Model Organisms

3 review(s)

SAB Members

SAB Comments

The receptor tyrosine kinase mesenchymal epithelial transition factor (MET) remains a target of interest primarily in the context of oncology where MET plays a critical role in cell growth, viability and metastasis.

Compound CPP1195 (AMG 337; cpd 23) shows single digit nanomolar inhibition of MET kinase activity through an ATP competitive mechanisms that has been shown to be highly selective when profiled against a panel of over 400 human kinases.

Additionally, a crystal structure of c-Met in complex with a structurally similar naphthyridinone inhibitor (compound 5) is referenced (PBD: 5EYC) providing evidence of binding mode and key features of the structural-activity relationship of the series. Consistent with the in vitro profiling results, a strength of the probe is the robust data from a structurally similar compound (inhibitor 5) showing activity in only 2 of a panel of 260 cell lines both of which were cells lines shown to have MET gene application and dependency.

Strong pharmacodynamic data at the level of site-specific phosphorylation for CPP1195 shows inhibition of MET activity in cultured human cells (PC3) and in vivo in mice with potential for oral delivery.

Feb 18 2021 - 9:23pm

Compound selectivity is outstanding for a kinase inhibitor with 0/402 kinases inhibited at 1 mM (PMID: 27196782). The plasma protein binding of AMG-337 is (relatively speaking) fairly low with unbound fractions of 17% in rat, 36% in mouse and 42% in human (PMID 26812066). This suggests that compound potency in cellular assays may not shift dramatically when serum concentration is varied. When profiled in a panel of 260 cancer cell lines, AMG-337 only affected the cell viability of two cell lines with elevated MET gene copy number: SNU-5 and Hs746T (PMID: 27196782). A 10 mg/kg dose of AMG337 was documented to provide >90% target inhibition in vivo for 12h in mice, resulting in > 90% tumor growth inhibition (PMID: 26812066). Notably, AMG-337 has been tested in Phase I and Phase II clinical trials (PMID 30425090, 30366938).

Feb 18 2021 - 9:26pm

AMG 337

Probe Information

Target Details

MET proto-oncogene receptor tyrosine kinase, AUTS9, DFNB97, HGFR, RCCP2, c-Met

Probe Details

In vitro validation

In cell validation

In vivo validation

Primary Reference

Supporting Organizations

Interested in supporting the portal?

Search form

AMG 337

Probe Information

Target Details

MET proto-oncogene receptor tyrosine kinase, AUTS9, DFNB97, HGFR, RCCP2, c-Met

Probe Details

In vitro validation

In cell validation

In vivo validation

Primary Reference

Supporting Organizations

Interested in supporting the portal?