Synthesis and biological evaluation of a series of novel inhibitor of Nek2/Hec1 analogues.
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.
Qiu
Xiao-Long
XL
Department of Biological Chemistry, School of Medicine, University of California, Irvine, California 92697, USA.
Li
Guideng
G
Wu
Guikai
G
Zhu
Jiewen
J
Zhou
Longen
L
Chen
Phang-Lang
PL
Chamberlin
A Richard
AR
Lee
Wen-Hwa
WH
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
D047428:Protein Kinase Inhibitors; C089441:NEK2 protein, human; D000072379:NIMA-Related Kinases; D017346:Protein Serine-Threonine Kinases