Journal of medicinal and pharmaceutical chemistry 2009-03-26

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

Xiao-Long Qiu, Guideng Li, Guikai Wu, Jiewen Zhu, Longen Zhou, Phang-Lang Chen, A Richard Chamberlin, Wen-Hwa Lee

文献索引：J. Med. Chem. 52(6) , 1757-67, (2009)

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摘要

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.