AMG-337
AMG-337 : ATP competitive inhibitor of MET
Structure
In Cells
In Model Organisms
SERP ratings and comments
SERP Ratings
(last updated: 14 Dec 2020 )
SERP Ratings
SERP Comments:
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
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 )