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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.

SUBMITTER: Yip KT 

PROVIDER: S-EPMC4858652 | biostudies-literature | 2016 May

REPOSITORIES: biostudies-literature

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Small Molecules Antagonise the MIA-Fibronectin Interaction in Malignant Melanoma.

Yip King Tuo KT   Zhong Xue Yin XY   Seibel Nadia N   Pütz Stefanie S   Autzen Jasmin J   Gasper Raphael R   Hofmann Eckhard E   Scherkenbeck Jürgen J   Stoll Raphael R  

Scientific reports 20160506


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 fu  ...[more]

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