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
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
PubMed ID: 25375378
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