title: Small Molecules Antagonise the MIA-Fibronectin Interaction in Malignant Melanoma.
abstract: Melanoma inhibitory activity (MIA), an extracellular protein highly expressed by malignant melanoma cells, plays an important functional role in melanoma development, progression, and metastasis. After its secretion, MIA directly interacts with extracellular matrix proteins, such as fibronectin (FN). By this mechanism, MIA actively facilitates focal cell detachment from surrounding structures and strongly promotes tumour cell invasion and migration. Hence, the molecular understanding of MIA's function provides a promising target for the development of new strategies in malignant melanoma therapy. Here, we describe for the first time the discovery of small molecules that are able to disrupt the MIA-FN complex by selectively binding to a new druggable pocket, which we could identify on MIA by structural analysis and fragment-based screening. Our findings may inspire novel drug discovery efforts aiming at a therapeutically effective treatment of melanoma by targeting MIA.
authors.affiliation: Ruhr University of Bochum, Faculty of Chemistry and Biochemistry, Bochum, 44780, Germany.
authors.forename: King Tuo
authors.initials: KT
authors.lastname: Yip
authors.affiliation: Ruhr University of Bochum, Faculty of Chemistry and Biochemistry, Bochum, 44780, Germany.
authors.forename: Xue Yin
authors.initials: XY
authors.lastname: Zhong
authors.affiliation: Ruhr University of Bochum, Faculty of Chemistry and Biochemistry, Bochum, 44780, Germany.
authors.forename: Nadia
authors.initials: N
authors.lastname: Seibel
authors.affiliation: Ruhr University of Bochum, Faculty of Chemistry and Biochemistry, Bochum, 44780, Germany.
authors.forename: Stefanie
authors.initials: S
authors.lastname: Pütz
authors.affiliation: University of Wuppertal, Faculty of Chemistry, Wuppertal, 42119, Germany.
authors.forename: Jasmin
authors.initials: J
authors.lastname: Autzen
authors.affiliation: Ruhr University of Bochum, Faculty of Biology and Biotechnology, Bochum, 44801, Germany.
authors.forename: Raphael
authors.initials: R
authors.lastname: Gasper
authors.affiliation: Ruhr University of Bochum, Faculty of Biology and Biotechnology, Bochum, 44801, Germany.
authors.forename: Eckhard
authors.initials: E
authors.lastname: Hofmann
authors.affiliation: University of Wuppertal, Faculty of Chemistry, Wuppertal, 42119, Germany.
authors.forename: Jürgen
authors.initials: J
authors.lastname: Scherkenbeck
authors.affiliation: Ruhr University of Bochum, Faculty of Chemistry and Biochemistry, Bochum, 44780, Germany.
authors.forename: Raphael
authors.initials: R
authors.lastname: Stoll
mesh_terms: D000970:Antineoplastic Agents / Q000302:isolation & purification* / Q000378:metabolism; D055808:Drug Discovery; D016326:Extracellular Matrix Proteins / Q000378:metabolism*; D005353:Fibronectins / Q000378:metabolism*; D006801:Humans; D009363:Neoplasm Proteins / Q000378:metabolism*; D011485:Protein Binding / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; D016326:Extracellular Matrix Proteins; D005353:Fibronectins; C090059:MIA protein, human; D009363:Neoplasm Proteins