title: Selection of Carbonic Anhydrase IX Inhibitors from One Million DNA-Encoded Compounds.
abstract: DNA-encoded chemical libraries, i.e., collections of compounds individually coupled to distinctive DNA fragments serving as amplifiable identification barcodes, represent a new tool for the de novo discovery of small molecule ligands to target proteins of pharmaceutical interest. Here, we describe the design and synthesis of a novel DNA-encoded chemical library containing one million small molecules. The library was synthesized by combinatorial assembly of three sets of chemical building blocks using Diels-Alder cycloadditions and by the stepwise build-up of the DNA barcodes. Model selections were performed to test library performance and to develop a statistical method for the analysis of high-throughput sequencing data. A library selection against carbonic anhydrase IX revealed a new class of submicromolar bis(sulfonamide) inhibitors. One of these inhibitors was synthesized in the absence of the DNA-tag and showed accumulation in hypoxic tumor tissue sections in vitro and tumor targeting in vivo.
authors.affiliation: Institute of Pharmaceutical Sciences, Department of Chemistry and Applied Biosciences, ETH Zurich, Switzerland.
authors.forename: Fabian
authors.initials: F
authors.lastname: Buller
authors.forename: Martina
authors.initials: M
authors.lastname: Steiner
authors.forename: Katharina
authors.initials: K
authors.lastname: Frey
authors.forename: Dennis
authors.initials: D
authors.lastname: Mircsof
authors.forename: Jorg
authors.initials: J
authors.lastname: Scheuermann
authors.forename: Markus
authors.initials: M
authors.lastname: Kalisch
authors.forename: Peter
authors.initials: P
authors.lastname: Buhlmann
authors.forename: Claudiu T
authors.initials: CT
authors.lastname: Supuran
authors.forename: Dario
authors.initials: D
authors.lastname: Neri
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy; D000951:Antigens, Neoplasm / Q000378:metabolism; D000071231:Carbonic Anhydrase IX; D002257:Carbonic Anhydrase Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D002256:Carbonic Anhydrases / Q000378:metabolism; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000188:drug therapy; D020650:Combinatorial Chemistry Techniques / Q000379:methods*; D004247:DNA / Q000737:chemistry; D005456:Fluorescent Dyes / Q000032:analysis; D015723:Gene Library; D059014:High-Throughput Nucleotide Sequencing; D057166:High-Throughput Screening Assays; D006801:Humans; D007700:Kinetics; D057054:Molecular Imaging; D058990:Molecular Targeted Therapy; D009368:Neoplasm Transplantation; D021281:Quantitative Structure-Activity Relationship; D054852:Small Molecule Libraries / Q000138:chemical synthesis* / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis* / Q000494:pharmacology
chemical_list: D000951:Antigens, Neoplasm; D002257:Carbonic Anhydrase Inhibitors; D005456:Fluorescent Dyes; D054852:Small Molecule Libraries; D013449:Sulfonamides; D004247:DNA; C089226:CA9 protein, human; D000071231:Carbonic Anhydrase IX; D002256:Carbonic Anhydrases