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

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.

SUBMITTER: Galkin AV 

PROVIDER: S-EPMC1765448 | biostudies-literature | 2007 Jan

REPOSITORIES: biostudies-literature

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

Galkin Anna V AV   Melnick Jonathan S JS   Kim Sungjoon S   Hood Tami L TL   Li Nanxin N   Li Lintong L   Xia Gang G   Steensma Ruo R   Chopiuk Greg G   Jiang Jiqing J   Wan Yongqin Y   Ding Peter P   Liu Yi Y   Sun Fangxian F   Schultz Peter G PG   Gray Nathanael S NS   Warmuth Markus M  

Proceedings of the National Academy of Sciences of the United States of America 20061221 1

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  ...[more]

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