Discovery of Small-Molecule Interleukin-2 Inhibitors from a DNA-Encoded Chemical Library

• Published in: Chemistry : a European journal 2012-06, Vol.18 (25), p.7729-7737
• Main Authors: Leimbacher, Markus, Zhang, Yixin, Mannocci, Luca, Stravs, Michael, Geppert, Tim, Scheuermann, Jörg, Schneider, Gisbert, Neri, Dario
• Format: Article
• Language: English
• Subjects: Antigens; Antigens, Neoplasm - drug effects; Binding; Carbonic Anhydrase Inhibitors - chemical synthesis; Carbonic Anhydrase Inhibitors - chemistry; Carbonic Anhydrase Inhibitors - pharmacology; Carbonic Anhydrase IX; Carbonic Anhydrases - drug effects; Chemistry; Combinatorial Chemistry Techniques; Cytokines; Deoxyribonucleic acid; Disrupting; DNA; DNA - chemistry; DNA - genetics; DNA-encoded chemical libraries; Drug Discovery; high-throughput screening; Humans; Inhibitors; Interleukin; Libraries; Ligands; Lymphokines - chemical synthesis; Lymphokines - chemistry; Lymphokines - pharmacology; Molecular Structure; Proteins; Small Molecule Libraries
• ISSN: 0947-6539; 1521-3765
• DOI: 10.1002/chem.201200952

Libraries of chemical compounds individually coupled to encoding DNA tags (DNA‐encoded chemical libraries) hold promise to facilitate exceptionally efficient ligand discovery. We constructed a high‐quality DNA‐encoded chemical library comprising 30 000 drug‐like compounds; this was screened in 170 different affinity capture experiments. High‐throughput sequencing allowed the evaluation of 120 million DNA codes for a systematic analysis of selection strategies and statistically robust identification of binding molecules. Selections performed against the tumor‐associated antigen carbonic anhydrase IX (CA IX) and the pro‐inflammatory cytokine interleukin‐2 (IL‐2) yielded potent inhibitors with exquisite target specificity. The binding mode of the revealed pharmacophore against IL‐2 was confirmed by molecular docking. Our findings suggest that DNA‐encoded chemical libraries allow the facile identification of drug‐like ligands principally to any protein of choice, including molecules capable of disrupting high‐affinity protein–protein interactions. Screen shots: Selections performed against the tumor‐associated antigen carbonic anhydrase IX and the pro‐inflammatory cytokine interleukin‐2 yielded potent inhibitors with exquisite target specificity (see figure). These findings suggest that DNA‐encoded chemical libraries allow the facile discovery of drug‐like ligands, including molecules capable of disrupting high‐affinity protein–protein interactions.