Pharmacophore guided discovery of small-molecule interleukin 15 inhibitors

Barbara Żyżyńska-Granica; Bartosz Trzaskowski; Szymon Niewieczerzał; Sławomir Filipek; Oliwia Zegrocka-Stendel; Małgorzata Dutkiewicz; Piotr Krzeczyński; Magdalena Kowalewska; Katarzyna Koziak

doi:10.1016/j.ejmech.2017.05.034

Pharmacophore guided discovery of small-molecule interleukin 15 inhibitors

Eur J Med Chem. 2017 Aug 18:136:543-547. doi: 10.1016/j.ejmech.2017.05.034. Epub 2017 May 12.

Authors

Barbara Żyżyńska-Granica¹, Bartosz Trzaskowski², Szymon Niewieczerzał³, Sławomir Filipek⁴, Oliwia Zegrocka-Stendel⁵, Małgorzata Dutkiewicz⁶, Piotr Krzeczyński⁷, Magdalena Kowalewska⁸, Katarzyna Koziak⁹

Affiliations

¹ Department of Pharmacodynamics, Centre for Preclinical Research and Technologies, Medical University of Warsaw, S. Banacha 1b, 02-097 Warsaw, Poland. Electronic address: b.zyzynska@gmail.com.
² University of Warsaw, Centre of New Technologies, S. Banacha 2c, 02-097 Warsaw, Poland. Electronic address: b.trzaskowski@cent.uw.edu.pl.
³ University of Warsaw, Centre of New Technologies, S. Banacha 2c, 02-097 Warsaw, Poland. Electronic address: szniew@gmail.com.
⁴ Faculty of Chemistry, Biological and Chemical Research Centre, University of Warsaw, Pasteura 1, 02-093 Warsaw, Poland. Electronic address: sfilipek@chem.uw.edu.pl.
⁵ Department of Immunology, Biochemistry and Nutrition, Centre for Preclinical Research and Technologies, Medical University of Warsaw, S. Banacha1b, 02-097 Warsaw, Poland. Electronic address: ostendel@wum.edu.pl.
⁶ Department of Immunology, Biochemistry and Nutrition, Centre for Preclinical Research and Technologies, Medical University of Warsaw, S. Banacha1b, 02-097 Warsaw, Poland. Electronic address: mdutkiewicz@wum.edu.pl.
⁷ Pharmaceutical Research Institute, Rydygiera 8, 01-793 Warsaw, Poland. Electronic address: p.krzeczynski@ifarm.eu.
⁸ Department of Immunology, Biochemistry and Nutrition, Centre for Preclinical Research and Technologies, Medical University of Warsaw, S. Banacha1b, 02-097 Warsaw, Poland; Department of Molecular and Translational Oncology, Maria Skłodowska-Curie Institute - Oncology Center, Roentgena 5, 02-781 Warsaw, Poland. Electronic address: mkowalewska@wum.edu.pl.
⁹ Department of Immunology, Biochemistry and Nutrition, Centre for Preclinical Research and Technologies, Medical University of Warsaw, S. Banacha1b, 02-097 Warsaw, Poland. Electronic address: katarzyna.koziak@wum.edu.pl.

PMID: 28535470
DOI: 10.1016/j.ejmech.2017.05.034

Abstract

Upregulation of interleukin 15 (IL-15) contributes directly i.a. to the development of inflammatory and autoimmune diseases. Selective blockade of IL-15 aimed to treat rheumatoid arthritis, psoriasis and other IL-15-related disorders has been recognized as an efficient therapeutic method. The aim of the study was to identify small molecules which would interact with IL-15 or its receptor IL-15Rα and inhibit the cytokine's activity. Based on the crystal structure of IL-15Rα·IL-15, we created pharmacophore models to screen the ZINC database of chemical compounds for potential IL-15 and IL-15Rα inhibitors. Twenty compounds with the highest predicted binding affinities were subjected to in vitro analysis using human peripheral blood mononuclear cells to validate in silico data. Twelve molecules efficiently reduced IL-15-dependent TNF-α and IL-17 synthesis. Among these, cefazolin - a safe first-generation cephalosporin antibiotic - holds the highest promise for IL-15-directed therapeutic applications.

Keywords: Cefazolin; IL-15; IL-15 inhibitor; IL-15Rα; IL-15Rα inhibitor; Interleukin-15; Psoriasis; Rheumatoid arthritis.

MeSH terms

Dose-Response Relationship, Drug
Humans
Interleukin-15 / antagonists & inhibitors*
Molecular Structure
Small Molecule Libraries / chemical synthesis
Small Molecule Libraries / chemistry
Small Molecule Libraries / pharmacology*
Structure-Activity Relationship

Substances

Interleukin-15
Small Molecule Libraries