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Developing antagonists for the Met-HGF/SF protein-protein interaction using a fragment-based approach

Item Type:Article
Title:Developing antagonists for the Met-HGF/SF protein-protein interaction using a fragment-based approach
Creators Name:Winter, A. and Sigurdardottir, A.G. and DiCara, D. and Valenti, G. and Blundell, T.L. and Gherardi, E.
Abstract:In many cancers, aberrant activation of the Met receptor tyrosine kinase leads to dissociation of cells from the primary tumor, causing metastasis. Accordingly, Met is a high-profile target for the development of cancer therapies, and progress has been made through development of small molecule kinase inhibitors and antibodies. However, both approaches pose significant challenges with respect to either target specificity (kinase inhibitors) or the cost involved in treating large patient cohorts (antibodies). Here, we use a fragment-based approach in order to target the protein-protein interaction (PPI) between the α-chain of hepatocyte growth factor/scatter factor (HGF/SF; the NK1 fragment) and its high-affinity binding site located on the Met Sema domain. Surface plasmon resonance was used for initial fragment library screening and hits were developed into larger compounds using substructure (similarity) searches. We identified compounds able to interfere with NK1 binding to Met, disrupt Met signaling, and inhibit tumorsphere generation and cell migration. Using molecular docking, we concluded that some of these compounds inhibit the PPI directly, whereas others act indirectly. Our results indicate that chemical fragments can efficiently target the HGF/SF-Met interface and may be used as building blocks for generating biologically active lead compounds. This strategy may have broad application for the development of a new class of Met inhibitors, namely receptor antagonists, and in general for the development of small molecule PPI inhibitors of key therapeutic targets when structural information is not available.
Keywords:Antineoplastic Agents, Antitumor Drug Screening Assays, Cell Line, Drug Discovery, Hepatocyte Growth Factor, Molecular Conformation, Molecular Models, Phosphorylation, Protein Binding, Protein Kinase Inhibitors, Proto-Oncogene Proteins c-akt, Proto-Oncogene Proteins c-met, Signal Transduction, Small Molecule Libraries, Structure-Activity Relationship, Animals, Mice
Source:Molecular Cancer Therapeutics
ISSN:1535-7163
Publisher:American Association for Cancer Research (U.S.A.)
Volume:15
Number:1
Page Range:3-14
Date:January 2016
Official Publication:https://doi.org/10.1158/1535-7163.MCT-15-0446
PubMed:View item in PubMed

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