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J Med Chem. 2009 Mar 26;52(6):1757-67. doi: 10.1021/jm8015969.

Synthesis and biological evaluation of a series of novel inhibitor of Nek2/Hec1 analogues.

Author information

1
Department of Biological Chemistry, School of Medicine, University of California, Irvine, California 92697, USA.

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.

PMID:
19243176
PMCID:
PMC2670097
DOI:
10.1021/jm8015969
[Indexed for MEDLINE]
Free PMC Article

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