Identification of NVP-TAE684, a potent, selective, and efficacious inhibitor of NPM-ALK.

Article Details

Citation

Copy to clipboard

Galkin AV, Melnick JS, Kim S, Hood TL, Li N, Li L, Xia G, Steensma R, Chopiuk G, Jiang J, Wan Y, Ding P, Liu Y, Sun F, Schultz PG, Gray NS, Warmuth M

Identification of NVP-TAE684, a potent, selective, and efficacious inhibitor of NPM-ALK.

Proc Natl Acad Sci U S A. 2007 Jan 2;104(1):270-5. Epub 2006 Dec 21.

PubMed ID

17185414 [ View in PubMed

]

Abstract

Constitutive overexpression and activation of NPM-ALK fusion protein [t(2:5)(p23;q35)] is a key oncogenic event that drives the survival and proliferation of anaplastic large-cell lymphomas (ALCLs). We have identified a highly potent and selective small-molecule ALK inhibitor, NVP-TAE684, which blocked the growth of ALCL-derived and ALK-dependent cell lines with IC(50) values between 2 and 10 nM. NVP-TAE684 treatment resulted in a rapid and sustained inhibition of phosphorylation of NPM-ALK and its downstream effectors and subsequent induction of apoptosis and cell cycle arrest. In vivo, NVP-TAE684 suppressed lymphomagenesis in two independent models of ALK-positive ALCL and induced regression of established Karpas-299 lymphomas. NVP-TAE684 also induced down-regulation of CD30 expression, suggesting that CD30 may be used as a biomarker of therapeutic NPM-ALK kinase activity inhibition.

DrugBank Data that Cites this Article

Drugs

Ceritinib

Drug Targets

Drug	Target	Kind	Organism	Pharmacological Action	Actions
Ceritinib	ALK tyrosine kinase receptor	Protein	Humans	Yes	Antagonist	Details