title: Discovery of small-molecule interleukin-2 inhibitors from a DNA-encoded chemical library.
abstract: 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.
authors.affiliation: Department of Chemistry and Applied Biosciences, Institute of Pharmaceutical Sciences, Wolfgang Pauli-Str. 10, 8093 Zürich, Switzerland.
authors.forename: Markus
authors.initials: M
authors.lastname: Leimbacher
authors.forename: Yixin
authors.initials: Y
authors.lastname: Zhang
authors.forename: Luca
authors.initials: L
authors.lastname: Mannocci
authors.forename: Michael
authors.initials: M
authors.lastname: Stravs
authors.forename: Tim
authors.initials: T
authors.lastname: Geppert
authors.forename: Jörg
authors.initials: J
authors.lastname: Scheuermann
authors.forename: Gisbert
authors.initials: G
authors.lastname: Schneider
authors.forename: Dario
authors.initials: D
authors.lastname: Neri
mesh_terms: D000951:Antigens, Neoplasm / Q000187:drug effects*; D000071231:Carbonic Anhydrase IX; D002257:Carbonic Anhydrase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002256:Carbonic Anhydrases / Q000187:drug effects*; D020650:Combinatorial Chemistry Techniques; D004247:DNA / Q000737:chemistry* / Q000235:genetics; D055808:Drug Discovery; D006801:Humans; D008024:Ligands; D008222:Lymphokines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D015394:Molecular Structure; D054852:Small Molecule Libraries
chemical_list: D000951:Antigens, Neoplasm; D002257:Carbonic Anhydrase Inhibitors; D008024:Ligands; D008222:Lymphokines; D054852:Small Molecule Libraries; C046147:interleukin 2 inhibitor; D004247:DNA; C089226:CA9 protein, human; D000071231:Carbonic Anhydrase IX; D002256:Carbonic Anhydrases