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	Fabian Buller, Martina Steiner, Katharina Frey, Dennis Mircsof, Jorg Scheuermann, Markus Kalisch, Peter Buhlmann, Claudiu T Supuran, Dario Neri
Journal	ACS chemical biology (ACS Chem Biol) Vol. 6 Issue 4 Pg. 336-44 (Apr 15 2011) ISSN: 1554-8937 [Electronic] United States
PMID	21186831 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References	Antigens, Neoplasm Carbonic Anhydrase Inhibitors Fluorescent Dyes Small Molecule Libraries Sulfonamides DNA CA9 protein, human Carbonic Anhydrase IX Carbonic Anhydrases
Topics	Adenocarcinoma (drug therapy) Antigens, Neoplasm (metabolism) Carbonic Anhydrase IX Carbonic Anhydrase Inhibitors (chemical synthesis, pharmacology) 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, pharmacology) Structure-Activity Relationship Sulfonamides (chemical synthesis, pharmacology)

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