title: Irreversible Nek2 kinase inhibitors with cellular activity.
abstract: A structure-based approach was used to design irreversible, cysteine-targeted inhibitors of the human centrosomal kinase, Nek2. Potent inhibition of Nek2 kinase activity in biochemical and cell-based assays required a noncatalytic cysteine residue (Cys22), located near the glycine-rich loop in a subset of human kinases. Elaboration of an oxindole scaffold led to our most selective compound, oxindole propynamide 16 (JH295). Propynamide 16 irreversibly inhibited cellular Nek2 without affecting the mitotic kinases, Cdk1, Aurora B, or Plk1. Moreover, 16 did not perturb bipolar spindle assembly or the spindle assembly checkpoint. To our knowledge, 16 is the first small molecule shown to inactivate Nek2 kinase activity in cells.
authors.affiliation: Program in Chemistry and Chemical Biology, Department of Cellular and Molecular Pharmacology, University of California, San Francisco, California 94158, United States.
authors.forename: Jeffrey C
authors.initials: JC
authors.lastname: Henise
authors.forename: Jack
authors.initials: J
authors.lastname: Taunton
mesh_terms: D002460:Cell Line; D002877:Chromosomes, Human / Q000187:drug effects / Q000648:ultrastructure; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008958:Models, Molecular; D000072379:NIMA-Related Kinases; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D008941:Spindle Apparatus / Q000187:drug effects / Q000648:ultrastructure; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D007211:Indoles; C561054:N-(3-((2-ethyl-4-methyl-1H-imidazol-5-yl)methylene)-2-oxoindolin-5-yl)propiolamide; C089441:NEK2 protein, human; D000072379:NIMA-Related Kinases; D017346:Protein Serine-Threonine Kinases