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 (<b>INH</b>) 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 <b>INH</b>, a series of <b>INH</b> analogues were designed, synthesized, and evaluated. Among these 33 newly synthesized analogues, three of them, <b>6</b>, <b>13</b>, and <b>21</b>, have 6−8 fold more potent cell killing activity than the previous lead compound <b>INH1</b>. Compounds <b>6</b> and <b>21</b> 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 <b>INH1</b>. This initial exploration of structural/functional relationship of <b>INH</b> may advance the progress for developing clinically applicable <b>INH</b> analogue.