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Inhibition of the MET Kinase Activity and Cell Growth in MET-Addicted Cancer Cells by Bi-Paratopic Linking.
Andres, Fabio; Iamele, Luisa; Meyer, Timo; Stüber, Jakob C; Kast, Florian; Gherardi, Ermanno; Niemann, Hartmut H; Plückthun, Andreas.
Afiliación
  • Andres F; Department of Biochemistry, University of Zurich, Winterthurerstrasse 190, 8057 Zurich, Switzerland.
  • Iamele L; Department of Molecular Medicine, University of Pavia, Italy.
  • Meyer T; Department of Chemistry, Bielefeld University, Germany.
  • Stüber JC; Department of Biochemistry, University of Zurich, Winterthurerstrasse 190, 8057 Zurich, Switzerland.
  • Kast F; Department of Biochemistry, University of Zurich, Winterthurerstrasse 190, 8057 Zurich, Switzerland.
  • Gherardi E; Department of Molecular Medicine, University of Pavia, Italy.
  • Niemann HH; Department of Chemistry, Bielefeld University, Germany.
  • Plückthun A; Department of Biochemistry, University of Zurich, Winterthurerstrasse 190, 8057 Zurich, Switzerland. Electronic address: plueckthun@bioc.uzh.ch.
J Mol Biol ; 431(10): 2020-2039, 2019 05 03.
Article en En | MEDLINE | ID: mdl-30930049
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.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Repetición de Anquirina / Proteínas Proto-Oncogénicas c-met / Inhibidores de Proteínas Quinasas Tipo de estudio: Prognostic_studies Límite: Humans Idioma: En Revista: J Mol Biol Año: 2019 Tipo del documento: Article País de afiliación: Suiza Pais de publicación: Países Bajos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Repetición de Anquirina / Proteínas Proto-Oncogénicas c-met / Inhibidores de Proteínas Quinasas Tipo de estudio: Prognostic_studies Límite: Humans Idioma: En Revista: J Mol Biol Año: 2019 Tipo del documento: Article País de afiliación: Suiza Pais de publicación: Países Bajos