Identification of NVP-TAE684, a potent, selective, and efficacious inhibitor of NPM-ALK
Copyright policy )Identification of NVP-TAE684, a potent, selective, and efficacious inhibitor of NPM-ALK
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.
- Scripps Research Institute United States
- Genomics Institute of the Novartis Research Foundation United States
STAT3 Transcription Factor, Cell Cycle, Ki-1 Antigen, Apoptosis, Mice, SCID, Protein-Tyrosine Kinases, Cell Line, Mice, Pyrimidines, STAT5 Transcription Factor, Animals, Humans, Lymphoma, Large B-Cell, Diffuse, Phosphorylation, Protein Kinase Inhibitors, Signal Transduction
STAT3 Transcription Factor, Cell Cycle, Ki-1 Antigen, Apoptosis, Mice, SCID, Protein-Tyrosine Kinases, Cell Line, Mice, Pyrimidines, STAT5 Transcription Factor, Animals, Humans, Lymphoma, Large B-Cell, Diffuse, Phosphorylation, Protein Kinase Inhibitors, Signal Transduction
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