NMR fragment-based screening for development of the CD44-binding small molecules

• Published in: Bioorganic chemistry 2019-02, Vol.82, p.284-289
• Main Authors: Pustuła, Marcin, Czub, Mirosława, Łabuzek, Beata, Surmiak, Ewa, Tomala, Marcin, Twarda-Clapa, Aleksandra, Guzik, Katarzyna, Popowicz, Grzegorz M., Holak, Tad A.
• Format: Article
• Language: English
• Subjects: CD44; Fragment-based screening; Hyaluronic acid; Small-molecular inhibitors
• ISSN: 0045-2068; 1090-2120
• DOI: 10.1016/j.bioorg.2018.10.043

[Display omitted] •Eight new small molecules with affinity for CD44 were found by fragment-based screening.•Binding constants for new hit compounds are between 0.66 and 2.65 mM.•A detailed analysis of the binding suggests the existence of two distinct binding modes.•In one of these modes the binding of compounds was blocked by the presence of hyaluronan. 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.