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.

• Authors: Anna V Galkin, 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
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 104 Issue 1 Pg. 270-5 (Jan 02 2007) ISSN: 0027-8424 [Print] United States
• PMID: 17185414 (Publication Type: Journal Article)

Chemical References

• Ki-1 Antigen
• NVP-TAE684
• Protein Kinase Inhibitors
• Pyrimidines
• STAT3 Transcription Factor
• STAT5 Transcription Factor
• p80(NPM-ALK) protein
• Protein-Tyrosine Kinases

Topics

• Animals
• Apoptosis (drug effects)
• Cell Cycle (drug effects)
• Cell Line
• Humans
• Ki-1 Antigen (analysis)
• Lymphoma, Large B-Cell, Diffuse (drug therapy)
• Mice
• Mice, SCID
• Phosphorylation
• Protein Kinase Inhibitors (pharmacology)
• Protein-Tyrosine Kinases (antagonists & inhibitors)
• Pyrimidines (pharmacology, therapeutic use)
• STAT3 Transcription Factor (metabolism)
• STAT5 Transcription Factor (metabolism)
• Signal Transduction (drug effects)