Qiu Xiao-Long, Li Guideng, Wu Guikai, Zhu Jiewen, Zhou Longen, Chen Phang-Lang, Chamberlin A Richard, Lee Wen-Hwa
Department of Biological Chemistry, School of Medicine, University of California, Irvine, California 92697, USA.
J Med Chem. 2009 Mar 26;52(6):1757-67. doi: 10.1021/jm8015969.
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.
癌症高表达蛋白1（Hec1）是一种在多种人类癌症中过度表达的癌基因。在有丝分裂途径中，一种靶向Hec1及其调节因子Nek2的小分子抑制剂（INH）被确定通过蛋白质降解使Hec1/Nek2功能失活，进而导致染色体错分离和细胞死亡。为了进一步提高INH的疗效，设计、合成并评估了一系列INH类似物。在这33种新合成的类似物中，其中三种，即6号、13号和21号，其细胞杀伤活性比先前的先导化合物INH1强6至8倍。选择化合物6号和21号来分析其潜在作用机制。它们直接靶向Hec1/Nek2途径，导致染色体排列错误以及细胞死亡，其机制与INH1相似。对INH结构/功能关系的这一初步探索可能会推动临床适用的INH类似物的开发进程。
