AMG-337

AMG-337 : ATP competitive inhibitor of MET

Structure

Information

  • MET
  • Inhibitor, ATP Competitive
  • 100 nM

In Vitro Validations

Uniprot ID: P08581
Target Class: Kinase
Target SubClass: TK
Potency: IC50
Potency Value: 1 nM
Potency Assay: TR-FRET (WT MET)
PDB ID for probe-target interaction (3D structure): --
Structure-activity relationship: yes
Target aliases:
Hepatocyte growth factor receptor, MET, MET_HUMAN, ...

DOI Reference: 10.1021/acs.jmedchem.5b01716

In Cell Validations

In Vivo Data

Off-Target Selectivity Assesments

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

I have extra information to add

SERP ratings and comments


SERP Ratings

In Cell Rating
In Model Organisms

(last updated: 14 Dec 2020 )

SERP Ratings

In Cell Rating
In Model Organisms

SERP 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.

(last updated: 14 Feb 2021 )

SERP Ratings

In Cell Rating
In Model Organisms

SERP Comments:

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).

(last updated: 18 Feb 2021 )