Selection of Carbonic Anhydrase IX Inhibitors from One Million DNA-Encoded Compounds

• Published in: ACS chemical biology 2011-04, Vol.6 (4), p.336-344
• Main Authors: Buller, Fabian, Steiner, Martina, Frey, Katharina, Mircsof, Dennis, Scheuermann, Jörg, Kalisch, Markus, Bühlmann, Peter, Supuran, Claudiu T, Neri, Dario
• Format: Article
• Language: English
• Subjects: Adenocarcinoma - drug therapy; Antigens, Neoplasm - metabolism; Carbonic Anhydrase Inhibitors - chemical synthesis; Carbonic Anhydrase Inhibitors - pharmacology; Carbonic Anhydrase IX; Carbonic Anhydrases - metabolism; Cell Line, Tumor; Colorectal Neoplasms - drug therapy; Combinatorial Chemistry Techniques - methods; DNA - chemistry; Fluorescent Dyes - analysis; Gene Library; High-Throughput Nucleotide Sequencing; High-Throughput Screening Assays; Humans; Kinetics; Molecular Imaging; Molecular Targeted Therapy; Neoplasm Transplantation; Quantitative Structure-Activity Relationship; Small Molecule Libraries - chemical synthesis; Small Molecule Libraries - pharmacology; Structure-Activity Relationship; Sulfonamides - chemical synthesis; Sulfonamides - pharmacology
• ISSN: 1554-8929; 1554-8937
• DOI: 10.1021/cb1003477

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.