Tags

Type your tag names separated by a space and hit enter

NMR fragment-based screening for development of the CD44-binding small molecules.
Bioorg Chem 2019; 82:284-289BC

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.

Authors+Show Affiliations

Faculty of Chemistry, Jagiellonian University, Gronostajowa 2, 30-387 Krakow, Poland.Faculty of Chemistry, Jagiellonian University, Gronostajowa 2, 30-387 Krakow, Poland.Faculty of Chemistry, Jagiellonian University, Gronostajowa 2, 30-387 Krakow, Poland.Faculty of Chemistry, Jagiellonian University, Gronostajowa 2, 30-387 Krakow, Poland.Faculty of Chemistry, Jagiellonian University, Gronostajowa 2, 30-387 Krakow, Poland.Faculty of Biochemistry, Biophysics, and Biotechnology, Jagiellonian University, Gronostajowa 7, 30-387 Krakow, Poland.Faculty of Chemistry, Jagiellonian University, Gronostajowa 2, 30-387 Krakow, Poland.Institute of Structural Biology, Helmholtz Zentrum München, Ingolstädter Landstrasse 1, 85764 Neuherberg, Germany.Faculty of Chemistry, Jagiellonian University, Gronostajowa 2, 30-387 Krakow, Poland. Electronic address: holak@chemia.uj.edu.pl.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

30396062

Citation

Pustuła, Marcin, et al. "NMR Fragment-based Screening for Development of the CD44-binding Small Molecules." Bioorganic Chemistry, vol. 82, 2019, pp. 284-289.
Pustuła M, Czub M, Łabuzek B, et al. NMR fragment-based screening for development of the CD44-binding small molecules. Bioorg Chem. 2019;82:284-289.
Pustuła, M., Czub, M., Łabuzek, B., Surmiak, E., Tomala, M., Twarda-Clapa, A., ... Holak, T. A. (2019). NMR fragment-based screening for development of the CD44-binding small molecules. Bioorganic Chemistry, 82, pp. 284-289. doi:10.1016/j.bioorg.2018.10.043.
Pustuła M, et al. NMR Fragment-based Screening for Development of the CD44-binding Small Molecules. Bioorg Chem. 2019;82:284-289. PubMed PMID: 30396062.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - NMR fragment-based screening for development of the CD44-binding small molecules. AU - Pustuła,Marcin, AU - Czub,Mirosława, AU - Łabuzek,Beata, AU - Surmiak,Ewa, AU - Tomala,Marcin, AU - Twarda-Clapa,Aleksandra, AU - Guzik,Katarzyna, AU - Popowicz,Grzegorz M, AU - Holak,Tad A, Y1 - 2018/10/25/ PY - 2018/08/10/received PY - 2018/10/22/revised PY - 2018/10/22/accepted PY - 2018/11/6/pubmed PY - 2018/11/6/medline PY - 2018/11/6/entrez KW - CD44 KW - Fragment-based screening KW - Hyaluronic acid KW - Small-molecular inhibitors SP - 284 EP - 289 JF - Bioorganic chemistry JO - Bioorg. Chem. VL - 82 N2 - 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. SN - 1090-2120 UR - https://www.unboundmedicine.com/medline/citation/30396062/NMR_fragment-based_screening_for_development_of_the_CD44-binding_small_molecules L2 - https://linkinghub.elsevier.com/retrieve/pii/S0045-2068(18)30838-1 DB - PRIME DP - Unbound Medicine ER -