title: Developing Antagonists for the Met-HGF/SF Protein-Protein Interaction Using a Fragment-Based Approach.
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.
authors.affiliation: Department of Molecular Cell Biology, The University of Cambridge, Cambridge, United Kingdom. aw284@le.ac.uk tom@cryst.bioc.cam.ac.uk.
authors.forename: Anja
authors.initials: A
authors.lastname: Winter
authors.affiliation: Department of Molecular Cell Biology, The University of Cambridge, Cambridge, United Kingdom.
authors.forename: Anna G
authors.initials: AG
authors.lastname: Sigurdardottir
authors.affiliation: MRC Centre, Cambridge, United Kingdom. Department of Oncology, The University of Cambridge, Cambridge Biomedical Campus, Cambridge, United Kingdom.
authors.forename: Danielle
authors.initials: D
authors.lastname: DiCara
authors.affiliation: Department of Cancer Research, Max Delbrueck Center for Molecular Medicine (MDC), Berlin, Germany.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Valenti
authors.affiliation: Department of Molecular Cell Biology, The University of Cambridge, Cambridge, United Kingdom. aw284@le.ac.uk tom@cryst.bioc.cam.ac.uk.
authors.forename: Tom L
authors.initials: TL
authors.lastname: Blundell
authors.affiliation: MRC Centre, Cambridge, United Kingdom.
authors.forename: Ermanno
authors.initials: E
authors.lastname: Gherardi
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D002460:Cell Line; D055808:Drug Discovery / Q000379:methods*; D004354:Drug Screening Assays, Antitumor / Q000379:methods; D017228:Hepatocyte Growth Factor / Q000378:metabolism*; D006801:Humans; D051379:Mice; D008958:Models, Molecular; D008968:Molecular Conformation; D010766:Phosphorylation; D011485:Protein Binding / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D019859:Proto-Oncogene Proteins c-met / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D054852:Small Molecule Libraries; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D054852:Small Molecule Libraries; D017228:Hepatocyte Growth Factor; D019859:Proto-Oncogene Proteins c-met; D051057:Proto-Oncogene Proteins c-akt