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

Constitutive overexpression and activation of the NPM-ALK fusion protein [t(2:5)(p23;q35)] is a critical 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 effectively blocked the growth of ALCL-derived and ALK-dependent cell lines, with IC(50) values ranging from 2 to 10 nM. Treatment with NVP-TAE684 led to rapid and sustained inhibition of NPM-ALK phosphorylation and its downstream effectors, ultimately inducing apoptosis and cell cycle arrest. In vivo, NVP-TAE684 suppressed lymphomagenesis in two distinct ALK-positive ALCL models and induced regression of established Karpas-299 lymphomas. Additionally, NVP-TAE684 caused downregulation of CD30 expression, suggesting that CD30 could serve as a biomarker for assessing the inhibition of NPM-ALK kinase activity in therapy.