Synthesis and Biological Evaluation of a Series of Novel Inhibitor of Nek2/Hec1 Analogues

• Published in: Journal of medicinal chemistry Vol. 52; no. 6; pp. 1757 - 1767
• Main Authors: Qiu, Xiao-Long, Li, Guideng, Wu, Guikai, Zhu, Jiewen, Zhou, Longen, Chen, Phang-Lang, Chamberlin, A. Richard, Lee, Wen-Hwa
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 26.03.2009; Amer Chemical Soc
• Subjects: Cell Line, Tumor; Chemistry, Medicinal; Flow Cytometry; Humans; Life Sciences & Biomedicine; Magnetic Resonance Spectroscopy; NIMA-Related Kinases; Pharmacology & Pharmacy; Protein Kinase Inhibitors - chemical synthesis; Protein Kinase Inhibitors - pharmacology; Protein-Serine-Threonine Kinases - antagonists & inhibitors; Science & Technology; Spectrometry, Mass, Electrospray Ionization; AURORA KINASES; CENTROSOME; STABILITY; NEK2A; HEC1; FAITHFUL CHROMOSOME SEGREGATION; MITOTIC CHECKPOINT; FAILURE; CANCER; KINETOCHORE-MICROTUBULE ATTACHMENT
• ISSN: 0022-2623; 1520-4804
• 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.