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

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

Author information

  • 1Kinase Lead Discovery, Department of Pharmacology, Genomics Institute of the Novartis Research Foundation, 10675 John Jay Hopkins Drive, San Diego, CA 92121, USA.

Erratum in

  • Proc Natl Acad Sci U S A. 2007 Feb 6;104(6):2025.

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.

PMID:
17185414
[PubMed - indexed for MEDLINE]
PMCID:
PMC1765448
Free PMC Article

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