Format

Send to

Choose Destination
J Mol Biol. 2019 May 3;431(10):2020-2039. doi: 10.1016/j.jmb.2019.03.024. Epub 2019 Mar 28.

Inhibition of the MET Kinase Activity and Cell Growth in MET-Addicted Cancer Cells by Bi-Paratopic Linking.

Author information

1
Department of Biochemistry, University of Zurich, Winterthurerstrasse 190, 8057 Zurich, Switzerland.
2
Department of Molecular Medicine, University of Pavia, Italy.
3
Department of Chemistry, Bielefeld University, Germany.
4
Department of Biochemistry, University of Zurich, Winterthurerstrasse 190, 8057 Zurich, Switzerland. Electronic address: plueckthun@bioc.uzh.ch.

Abstract

MET, the product of the c-MET proto-oncogene, and its ligand hepatocyte growth factor/scatter factor (HGF/SF) control survival, proliferation and migration during development and tissue regeneration. HGF/SF-MET signaling is equally crucial for growth and metastasis of a variety of human tumors, but resistance to small-molecule inhibitors of MET kinase develops rapidly and therapeutic antibody targeting remains challenging. We made use of the designed ankyrin repeat protein (DARPin) technology to develop an alternative approach for inhibiting MET. We generated a collection of MET-binding DARPins covering epitopes in the extracellular MET domains and created comprehensive sets of bi-paratopic fusion proteins. This new class of molecules efficiently inhibited MET kinase activity and downstream signaling, caused receptor downregulation and strongly inhibited the proliferation of MET-dependent gastric carcinoma cells carrying MET locus amplifications. MET-specific bi-paratopic DARPins may represent a novel and potent strategy for therapeutic targeting of MET and other receptors, and this study has elucidated their mode of action.

KEYWORDS:

DARPins; MET; X-ray crystallography; biparatopic; protein engineering

PMID:
30930049
DOI:
10.1016/j.jmb.2019.03.024

Supplemental Content

Full text links

Icon for Elsevier Science
Loading ...
Support Center