N-[4-(2,4-Dimethylphenyl)-2-thiazolyl]benzamidehydrochloride

Uses

N-[4-(2,4-Dimethylphenyl)-2-thiazolyl]benzamide is a small molecule that targets the Hec1/Nek2 pathway and was found to effectively inhibit the proliferation of multiple human breast cancer cell lines in culture and in animal.

General Description

A cell-permeable thiazolyl benzamide compound that directly binds Hec1 and disrupts Hec1/Nek2 complex formation, resulting in defective Hec1 kinetochores localization and cellular Nek2 destabilization/downregulation. Shown to induce a transient mitotic arrest in HeLa cultures and inhibit the proliferation of 10 breast cancer cell lines (GI₅₀ of 10-21 μM) as well as the cervical HeLa and colon HCT116 cancer lines, while exhibiting reduced potency against the noncancerous MCF10A line (GI₅₀ = 41 μM). Reported to suppress the MDA-MB-468-derived tumor growth (by ~53% and ~75% 3 wks after a 7-wk treatment period with 50 mg/kg and 100 mg/kg INH1, repectively, i.p.) in a murine breast cancer model in vivo.

Biological Activity

inh1 is a potent inhibitor of hec1/nek2 [1].hec1 is an oncogene that involved in spindle checkpoint signaling and is overexpressed in many human cancers. nek2 is serine/threonine-protein kinase that phosphorylates hec1, which is critical for its mitotic function and cell survival [1].inh1 is a potent inhibitor of hec1/nek2 via directly binding to hec1. inh1 (1 and 20 μm) inhibited the ability of chip-immobilized hec1 binding to free nek2 by 39% and 55% but didn’t affect immobilized nek2 binding to free hec1, which suggested that inh1 directly bound to hec1. in the lysate from cells treated with inh1 (25 μm), the coimmunoprecipitate of hec1 with nek2 was inhibited, suggesting that inh1 disrupted the hec1/nek2 complex. inh1 (25 μm) significantly reduced cellular nek2 protein level by 80-90% in a time- and dose-dependent way and reduced kinetochore-bound hec1 pool by 55%. in human breast cancer cell lines, inh1 inhibited cell proliferation with gi50 values of 10-21 μm. in hela cells, inh1 increased the mitotic index by 2-fold and induced mitotic abnormalities [1].in nude mice xenografted breast cancer, inh1 inhibited tumor growth [1].

References

[1]. wu g, qiu xl, zhou l, et al. small molecule targeting the hec1/nek2 mitotic pathway suppresses tumor cell growth in culture and in animal. cancer res, 2008, 68(20): 8393-8399.