NMR fragment-based screening for development of the CD44-binding small molecules |
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| Institution: | 1. Faculty of Chemistry, Jagiellonian University, Gronostajowa 2, 30-387 Krakow, Poland;2. Institute of Structural Biology, Helmholtz Zentrum München, Ingolstädter Landstrasse 1, 85764 Neuherberg, Germany;3. Faculty of Biochemistry, Biophysics, and Biotechnology, Jagiellonian University, Gronostajowa 7, 30-387 Krakow, Poland;1. Department of Biochemistry and Molecular Biology, University of Melbourne, Parkville, Victoria 3010, Australia;2. Bio21 Institute of Molecular Science and Biotechnology, University of Melbourne, Parkville, Victoria 3010, Australia;3. Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia;4. Department of Surgery, University of Melbourne, Royal Melbourne Hospital, Parkville, Victoria 3052, Australia;1. Univ. Bordeaux, F-33170 Gradignan, France;2. CNRS, IN2P3, CENBG, UMR 5797, F-33170 Gradignan, France;1. Biotechnology Program, ENMH-IPN, Mexico City, Mexico;2. Molecular Biomedicine Program, ENMH-IPN, Mexico City, Mexico;3. Genomics Sciences Program, UACM, Mexico City, Mexico;4. Subdirección de Enseñanza e Investigación, Hospital Regional de Alta Especialidad de Oaxaca, Oaxaca, Mexico;3. Department of Anatomy and Cell Biology and the Medical Research Center Oulu, Institute of Biomedicine, University of Oulu, FI-90014 Oulu, Finland;4. the Department of Biochemistry, Institute for Research in Immunology and Cancer and Groupe de Recherche Universitaire sur le Médicament, Université de Montréal, Montréal, Québec H3C 3J7, Canada |
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| Abstract: | The cell-surface protein CD44, a primary receptor for hyaluronic acid (HA), is one of the most promising targets for cancer therapies. It is prominently involved in the process of tumor growth and metastasis. The possibility of modulating the CD44-HA interaction with a pharmacological inhibitor is therefore of great importance, yet until now there are only few small molecules reported to bind to CD44. Here, we describe the results of the NMR fragment-based screening conducted against CD44 by which we found eight new hit compounds that bind to the receptor with the affinity in milimolar range. The NMR-based characterization revealed that there are two possible binding modes for these compounds, and for some of them the binding is no longer possible in the presence of hyaluronic acid. This could provide an interesting starting point for the development of new high-affinity ligands targeting the CD44-HA axis. |
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| Keywords: | CD44 Hyaluronic acid Small-molecular inhibitors Fragment-based screening |
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