title: Synthesis and biological evaluation of a series of novel inhibitor of Nek2/Hec1 analogues.
abstract: High expression in cancer 1 (Hec1) is an oncogene overly expressed in many human cancers. Small molecule inhibitor of Nek2/Hec1 (INH) targeting the Hec1 and its regulator, Nek2, in the mitotic pathway, was identified to inactivate Hec1/Nek2 function mediated by protein degradation that subsequently leads to chromosome mis-segregation and cell death. To further improve the efficacy of INH, a series of INH analogues were designed, synthesized, and evaluated. Among these 33 newly synthesized analogues, three of them, 6, 13, and 21, have 6-8 fold more potent cell killing activity than the previous lead compound INH1. Compounds 6 and 21 were chosen for analyzing the underlying action mechanism. They target directly the Hec1/Nek2 pathway and cause chromosome mis-alignment as well as cell death, a mechanism similar to that of INH1. This initial exploration of structural/functional relationship of INH may advance the progress for developing clinically applicable INH analogue.
authors.affiliation: Department of Biological Chemistry, School of Medicine, University of California, Irvine, California 92697, USA.
authors.forename: Xiao-Long
authors.initials: XL
authors.lastname: Qiu
authors.forename: Guideng
authors.initials: G
authors.lastname: Li
authors.forename: Guikai
authors.initials: G
authors.lastname: Wu
authors.forename: Jiewen
authors.initials: J
authors.lastname: Zhu
authors.forename: Longen
authors.initials: L
authors.lastname: Zhou
authors.forename: Phang-Lang
authors.initials: PL
authors.lastname: Chen
authors.forename: A Richard
authors.initials: AR
authors.lastname: Chamberlin
authors.forename: Wen-Hwa
authors.initials: WH
authors.lastname: Lee
mesh_terms: D045744:Cell Line, Tumor; D005434:Flow Cytometry; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D000072379:NIMA-Related Kinases; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D021241:Spectrometry, Mass, Electrospray Ionization
chemical_list: D047428:Protein Kinase Inhibitors; C089441:NEK2 protein, human; D000072379:NIMA-Related Kinases; D017346:Protein Serine-Threonine Kinases