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Nat Chem Biol. 2014 Jan;10(1):29-34. doi: 10.1038/nchembio.1381. Epub 2013 Nov 10.

Chemical inhibition of prometastatic lysyl-tRNA synthetase-laminin receptor interaction.

Author information

1
1] Medicinal Bioconvergence Research Center, Seoul National University, Seoul, Korea. [2] Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul, Korea. [3].
2
1] Medicinal Bioconvergence Research Center, Seoul National University, Seoul, Korea. [2] Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul, Korea.
3
Department of Cancer Biology, The Scripps Research Institute, Scripps Florida, Jupiter, Florida, USA.
4
Department of Chemistry and Biochemistry, Florida State University, Tallahassee, Florida, USA.
5
Ion Cyclotron Resonance Program, National High Magnetic Field Laboratory, Florida State University, Tallahassee, Florida, USA.
6
College of Pharmacy, Korea University, Sejong, Korea.
7
1] Medicinal Bioconvergence Research Center, Seoul National University, Seoul, Korea. [2] Wellman Center for Photomedicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.
8
Yuhan Research Institute, Yongin, Korea.
9
Department of Neurosurgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
10
Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul, Korea.
11
College of Pharmacy, Duksung Women's University, Seoul, Korea.
12
Medicinal Bioconvergence Research Center, Seoul National University, Seoul, Korea.
13
Translational Research Center for Protein Function Control, Department of Biotechnology and WCU Department of Biomedical Sciences, Yonsei University, Seoul, Korea.
14
BRI, Korea Institute of Science and Technology, Seoul, Korea.
15
The National Center for Drug Screening, Zhangjiang High-Tech Park, Shanghai, China.
16
1] Medicinal Bioconvergence Research Center, Seoul National University, Seoul, Korea. [2] Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul, Korea. [3] World Class University Department of Molecular Medicine and Biopharmaceutical Sciences, Seoul National University, Seoul, Korea.

Abstract

Lysyl-tRNA synthetase (KRS), a protein synthesis enzyme in the cytosol, relocates to the plasma membrane after a laminin signal and stabilizes a 67-kDa laminin receptor (67LR) that is implicated in cancer metastasis; however, its potential as an antimetastatic therapeutic target has not been explored. We found that the small compound BC-K-YH16899, which binds KRS, impinged on the interaction of KRS with 67LR and suppressed metastasis in three different mouse models. The compound inhibited the KRS-67LR interaction in two ways. First, it directly blocked the association between KRS and 67LR. Second, it suppressed the dynamic movement of the N-terminal extension of KRS and reduced membrane localization of KRS. However, it did not affect the catalytic activity of KRS. Our results suggest that specific modulation of a cancer-related KRS-67LR interaction may offer a way to control metastasis while avoiding the toxicities associated with inhibition of the normal functions of KRS.

PMID:
24212136
PMCID:
PMC4021855
DOI:
10.1038/nchembio.1381
[Indexed for MEDLINE]
Free PMC Article

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