期刊
JOURNAL OF BIOLOGICAL CHEMISTRY
卷 294, 期 41, 页码 15172-15175出版社
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.AC119.010790
关键词
protein degradation; protein turnover; proteolysis; proteasome; ubiquitin; drug design; drug development; protein targeting; drug therapy; N-end rule; PROTAC
资金
- Cancer Prevention Institute of Texas [RP170686, RP180769, RP160844]
- Mays Cancer Center
- William & Ella Owens Medical Research Foundation
- National Center for Advancing Translational Science [UL1TR001120]
- Peking-Tsinghua Center for Life Sciences
- Beijing National Laboratory for Molecular Sciences
- National Science Foundation of China [31521004, 21672011, 21822101]
- Ministry of Science and Technology [2017YFA0104000]
Proteolysis targeting chimeras (PROTACs) are bivalent molecules that bring a cellular protein to a ubiquitin ligase E3 for ubiquitination and subsequent degradation. Although PROTAC has emerged as a promising therapeutic means for cancers as it rewires the ubiquitin pathway to destroy key cancer regulators, the degradation signals/pathways for PROTACs remain underdeveloped. Here we append single amino acids, the simplest degradation signal, to a ligand specific for estrogen-related receptor ? (ERR?) and demonstrate their utility in ERR? knockdown via the N-end rule pathway and also their efficiency in the growth inhibition of breast cancer cells. The modular design described offers unique advantages including smaller molecular size with shortest degradation sequences and degradation speed modulation with different amino acids. Our study expands the repertoire of limited ubiquitin pathways currently available for PROTACs and could be easily adapted for broad use in targeted protein degradation.
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