Hec1 is a conserved mitotic regulator critical for spindle checkpoint control, kinetochore functionality, and cell survival. Overexpression of Hec1 has been detected in a variety of human cancers and is linked to poor prognosis of primary breast cancers. Through a chemical genetic screening, we have identified a small molecule, N-(4-[2,4-dimethyl-phenyl]-thiazol-2-yl)-benzamide (INH1), which specifically disrupts the Hec1/Nek2 interaction via direct Hec1 binding. Treating cells with INH1 triggered reduction of kinetochore-bound Hec1 as well as global Nek2 protein level, consequently leading to metaphase chromosome misalignment, spindle aberrancy, and eventual cell death. INH1 effectively inhibited the proliferation of multiple human breast cancer cell lines in culture (GI 50 , 10-21 Mmol/L). Furthermore, treatment with INH1 retarded tumor growth in a nude mouse model bearing xenografts derived from the human breast cancer line MDA-MB-468, with no apparent side effects. This study suggests that the Hec1/Nek2 pathway may serve as a novel mitotic target for cancer intervention by small compounds. [Cancer Res 2008;68(20):8393-9]
Introduction of fluorine atoms or fluorine‐containing groups into amino acids has attracted much attention from bioorganic and medicinal chemists because the resulting fluorinated amino acids have found wide application as potential enzyme inhibitors and antitumor (antibacterial) agents. Additionally, it is well known that replacement of naturally occurring amino acid(s) in some peptide chains with their fluorinated counterparts can significantly increase specific protein–ligand or protein–protein interactions, leading to increases in the proteolytic and thermal stabilities of peptide compounds and, as a result, promote their therapeutic properties. This microreview summarizes important advances in the synthesis of fluorinated amino acids since 2005. The contents are simply divided into three groups on the basis of amino acid types: fluorinated α‐amino acids (F‐αAAs), fluorinated β‐amino acids (F‐βAAs), and fluorinated cyclic amino acids (F‐CAAs).
Hec1 (High Expression in Cancer 1) is an oncogene overly expressed in many human cancers. Small molecule INH (Inhibitor of Nek2/Hec1) 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 was designed, synthesized and evaluated. Among these 33 newlysynthesized 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.
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