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

Basic Information

ID: ALA1152785

Journal: J Med Chem

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

Authors: Qiu XL, Li G, Wu G, Zhu J, Zhou L, Chen PL, Chamberlin AR, Lee WH.

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.

CiteXplore: 19243176

DOI: 10.1021/jm8015969

Patent ID: ┄