2. Academic Validation
  3. Identification of NVP-TAE684, a potent, selective, and efficacious inhibitor of NPM-ALK

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. doi: 10.1073/pnas.0609412103.
Anna V Galkin 1,  Jonathan S Melnick,  Sungjoon Kim,  Tami L Hood,  Nanxin Li,  Lintong Li,  Gang Xia,  Ruo Steensma,  Greg Chopiuk,  Jiqing Jiang,  Yongqin Wan,  Peter Ding,  Yi Liu,  Fangxian Sun,  Peter G Schultz,  Nathanael S Gray,  Markus Warmuth
Affiliations

Affiliation

  • 1 Kinase Lead Discovery, Department of Pharmacology, Genomics Institute of the Novartis Research Foundation, 10675 John Jay Hopkins Drive, San Diego, CA 92121, USA.
PMID: 17185414 DOI: 10.1073/pnas.0609412103
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.

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