Small molecule targeting the Hec1/Nek2 mitotic pathway suppresses tumor cell growth in culture and in animal.

Abstract

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 micromol/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.

• Authors: Guikai Wu, Xiao-Long Qiu, Longen Zhou, Jiewen Zhu, Richard Chamberlin, Johnson Lau, Phang-Lang Chen, Wen-Hwa Lee
• Journal: Cancer research (Cancer Res) Vol. 68 Issue 20 Pg. 8393-9 (Oct 15 2008) ISSN: 1538-7445 [Electronic] United States
• PMID: 18922912 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Antineoplastic Agents
• Benzamides
• Cytoskeletal Proteins
• Indoles
• NDC80 protein, human
• Nuclear Proteins
• Thiazoles
• Valerates
• methyl 5-(5,6-dichloro-2-indolyl)-2-methoxy-2,4-pentadienoate
• NEK2 protein, human
• NIMA-Related Kinases
• Protein Serine-Threonine Kinases

Topics

• Animals
• Antineoplastic Agents (pharmacology)
• Benzamides (pharmacology, therapeutic use)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Cytoskeletal Proteins
• Female
• Humans
• Indoles
• Mammary Neoplasms, Experimental (drug therapy)
• Mice
• Mice, Inbred BALB C
• Mitosis (drug effects)
• NIMA-Related Kinases
• Neoplasm Transplantation
• Nuclear Proteins (antagonists & inhibitors)
• Protein Serine-Threonine Kinases (antagonists & inhibitors)
• Signal Transduction (drug effects)
• Thiazoles (pharmacology, therapeutic use)
• Transplantation, Heterologous
• Valerates