title: 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.affiliation: Kinase Lead Discovery, Department of Pharmacology, Genomics Institute of the Novartis Research Foundation, 10675 John Jay Hopkins Drive, San Diego, CA 92121, USA.
authors.forename: Anna V
authors.initials: AV
authors.lastname: Galkin
authors.forename: Jonathan S
authors.initials: JS
authors.lastname: Melnick
authors.forename: Sungjoon
authors.initials: S
authors.lastname: Kim
authors.forename: Tami L
authors.initials: TL
authors.lastname: Hood
authors.forename: Nanxin
authors.initials: N
authors.lastname: Li
authors.forename: Lintong
authors.initials: L
authors.lastname: Li
authors.forename: Gang
authors.initials: G
authors.lastname: Xia
authors.forename: Ruo
authors.initials: R
authors.lastname: Steensma
authors.forename: Greg
authors.initials: G
authors.lastname: Chopiuk
authors.forename: Jiqing
authors.initials: J
authors.lastname: Jiang
authors.forename: Yongqin
authors.initials: Y
authors.lastname: Wan
authors.forename: Peter
authors.initials: P
authors.lastname: Ding
authors.forename: Yi
authors.initials: Y
authors.lastname: Liu
authors.forename: Fangxian
authors.initials: F
authors.lastname: Sun
authors.forename: Peter G
authors.initials: PG
authors.lastname: Schultz
authors.forename: Nathanael S
authors.initials: NS
authors.lastname: Gray
authors.forename: Markus
authors.initials: M
authors.lastname: Warmuth
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D002460:Cell Line; D006801:Humans; D017730:Ki-1 Antigen / Q000032:analysis; D016403:Lymphoma, Large B-Cell, Diffuse / Q000188:drug therapy*; D051379:Mice; D016513:Mice, SCID; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D011743:Pyrimidines / Q000494:pharmacology* / Q000627:therapeutic use; D050796:STAT3 Transcription Factor / Q000378:metabolism; D050799:STAT5 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D017730:Ki-1 Antigen; C516714:NVP-TAE684; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D050796:STAT3 Transcription Factor; D050799:STAT5 Transcription Factor; C107023:p80(NPM-ALK) protein; D011505:Protein-Tyrosine Kinases