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

Galkin, Anna and Melnick, Jonathan S and Kim, Sungjoon and Hood, Tami and Li, Nanxin and Li, Lintong and Xia, Gang and Steensma, Ruo and Chopiuk, Gregory and Jiang, Jiqing and Wan, Yongqin and Ding, Peter and Liu, Yi and Sun, Fangxian and Schultz, Peter and Gray, Nathanael and Warmuth, Markus (2007) Identification of NVP-TAE684, a potent, selective, and efficacious inhibitor of NPM-ALK. Proceedings of the National Academy of Sciences of the United States of America, 104 (1). pp. 270-275. ISSN 0027-8424

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.

Item Type: Article
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Additional Information: free full text version at publisher's official URL and at PubMedCentral; can archive pre-print and post-print; Publisher's version/PDF cannot be used
Keywords: anaplastic large-cell lymphoma, CD30, kinase inhibitor
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Date Deposited: 14 Dec 2009 14:05
Last Modified: 31 Jan 2013 01:27
URI: https://oak.novartis.com/id/eprint/126

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