PMID- 30090230 OWN - NLM STAT- PubMed-not-MEDLINE LR - 20200930 IS - 2041-6520 (Print) IS - 2041-6539 (Electronic) IS - 2041-6520 (Linking) VI - 6 IP - 11 DP - 2015 Nov 1 TI - Exploring the chemical space of the lysine-binding pocket of the first kringle domain of hepatocyte growth factor/scatter factor (HGF/SF) yields a new class of inhibitors of HGF/SF-MET binding. PG - 6147-6157 LID - 10.1039/c5sc02155c [doi] AB - The growth/motility factor hepatocyte growth factor/scatter factor (HGF/SF) and its receptor, the tyrosine kinase MET, constitute a signalling system essential for embryogenesis and for tissue/organ regeneration in post-natal life. HGF/SF-MET signalling, however, also plays a key role in the onset of metastasis of a large number of human tumours. Both HGF/SF and MET are high molecular weight proteins that bury an extensive interface upon complex formation and thus constitute a challenging target for the development of low molecular weight inhibitors. Here we have used surface plasmon resonance (SPR), nuclear magnetic resonance (NMR) and X-ray crystallography to screen a diverse fragment library of 1338 members as well as a range of piperazine-like compounds. Several small molecules were found to bind in the lysine-binding pocket of the kringle 1 domain of HGF/SF and its truncated splice variant NK1. We have defined the binding mode of these compounds, explored their biological activity and we show that selected fragments inhibit MET downstream signalling. Thus we demonstrate that targeting the lysine-binding pocket of NK1 is an effective strategy to generate MET receptor antagonists and we offer proof of concept that the HGF/SF-MET interface may be successfully targeted with small molecules. These studies have broad implications for the development of HGF/SF-MET therapeutics and cancer treatment. FAU - Sigurdardottir, A G AU - Sigurdardottir AG AUID- ORCID: 0000-0002-5225-397X AD - Department of Biochemistry , University of Cambridge , 80 Tennis Court Road , Cambridge , CB2 1GA , UK . Email: tlb20@cam.ac.uk ; Email: sigurdar@mrc-lmb.cam.ac.uk. FAU - Winter, A AU - Winter A AD - Department of Biochemistry , University of Cambridge , 80 Tennis Court Road , Cambridge , CB2 1GA , UK . Email: tlb20@cam.ac.uk ; Email: sigurdar@mrc-lmb.cam.ac.uk. FAU - Sobkowicz, A AU - Sobkowicz A AD - Medical Research Council (MRC) Center , Hills Road , Cambridge , CB2 0QH , UK. FAU - Fragai, M AU - Fragai M AD - Magnetic Resonance Center (CERM) and Department of Chemistry , University of Florence , Via L. Sacconi 6, 50019 Sesto Fiorentino , Florence , Italy. FAU - Chirgadze, D AU - Chirgadze D AD - Department of Biochemistry , University of Cambridge , 80 Tennis Court Road , Cambridge , CB2 1GA , UK . Email: tlb20@cam.ac.uk ; Email: sigurdar@mrc-lmb.cam.ac.uk. FAU - Ascher, D B AU - Ascher DB AD - Department of Biochemistry , University of Cambridge , 80 Tennis Court Road , Cambridge , CB2 1GA , UK . Email: tlb20@cam.ac.uk ; Email: sigurdar@mrc-lmb.cam.ac.uk. FAU - Blundell, T L AU - Blundell TL AUID- ORCID: 0000-0002-2708-8992 AD - Department of Biochemistry , University of Cambridge , 80 Tennis Court Road , Cambridge , CB2 1GA , UK . Email: tlb20@cam.ac.uk ; Email: sigurdar@mrc-lmb.cam.ac.uk. FAU - Gherardi, E AU - Gherardi E AD - Medical Research Council (MRC) Center , Hills Road , Cambridge , CB2 0QH , UK. AD - Unit of Immunology and General Pathology , Department of Molecular Medicine , University of Pavia , 9 via A Ferrata , 27100 Pavia , Italy. LA - eng PT - Journal Article DEP - 20150731 PL - England TA - Chem Sci JT - Chemical science JID - 101545951 PMC - PMC6054100 EDAT- 2015/11/01 00:00 MHDA- 2015/11/01 00:01 PMCR- 2015/07/31 CRDT- 2018/08/10 06:00 PHST- 2015/06/15 00:00 [received] PHST- 2015/07/29 00:00 [accepted] PHST- 2018/08/10 06:00 [entrez] PHST- 2015/11/01 00:00 [pubmed] PHST- 2015/11/01 00:01 [medline] PHST- 2015/07/31 00:00 [pmc-release] AID - c5sc02155c [pii] AID - 10.1039/c5sc02155c [doi] PST - ppublish SO - Chem Sci. 2015 Nov 1;6(11):6147-6157. doi: 10.1039/c5sc02155c. Epub 2015 Jul 31.