Cancer cell death induced by novel small molecules degrading the TACC3 protein via the ubiquitin-proteasome pathway.

The selective degradation of target proteins with small molecules is a novel approach to the treatment of various diseases, including cancer. We have developed a protein knockdown system with a series of hybrid small compounds that induce the selective degradation of target proteins via the ubiquitin-proteasome pathway. In this study, ...
we designed and synthesized novel small molecules called SNIPER(TACC3)s, which target the spindle regulatory protein transforming acidic coiled-coil-3 (TACC3). SNIPER(TACC3)s induce poly-ubiquitylation and proteasomal degradation of TACC3 and reduce the TACC3 protein level in cells. Mechanistic analysis indicated that the ubiquitin ligase APC/C(CDH1) mediates the SNIPER(TACC3)-induced degradation of TACC3. Intriguingly, SNIPER(TACC3) selectively induced cell death in cancer cells expressing a larger amount of TACC3 protein than normal cells. These results suggest that protein knockdown of TACC3 by SNIPER(TACC3) is a potential strategy for treating cancers overexpressing the TACC3 protein.
Mesh Terms:
Antineoplastic Agents, Cell Death, Cell Line, Tumor, Drug Design, Gene Expression Regulation, Neoplastic, HT29 Cells, Humans, Killer Factors, Yeast, Leucine, MCF-7 Cells, Microtubule-Associated Proteins, Molecular Targeted Therapy, Proteasome Endopeptidase Complex, Saccharomyces cerevisiae Proteins, Small Molecule Libraries, Ubiquitin, Ubiquitination
Cell Death Dis
Date: Nov. 06, 2014
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