Journal
CANCER RESEARCH
Volume 68, Issue 20, Pages 8393-8399Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/0008-5472.CAN-08-1915
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Funding
- NIH [CA107568]
- Department of Defense
- Susan Komen Breast Cancer Foundation
- California Breast Cancer Research Program
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Hec1 is a conserved mitotic regulator critical for spindle checkpoint control, kinetochore functionality, and cell survival. Overexpression of Heel 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 Heel binding. Treating cells with INH1 triggered reduction of kinetochore-bound Heel 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 mu mol/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]
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