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

ACS Chem Biol. 2011 Apr 15;6(4):336-44. doi: 10.1021/cb1003477. Epub 2011 Jan 12.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenocarcinoma / drug therapy
  • Antigens, Neoplasm* / metabolism
  • Carbonic Anhydrase IX
  • Carbonic Anhydrase Inhibitors / chemical synthesis*
  • Carbonic Anhydrase Inhibitors / 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*
  • Small Molecule Libraries / pharmacology
  • Structure-Activity Relationship
  • Sulfonamides / chemical synthesis*
  • Sulfonamides / pharmacology

Substances

  • Antigens, Neoplasm
  • Carbonic Anhydrase Inhibitors
  • Fluorescent Dyes
  • Small Molecule Libraries
  • Sulfonamides
  • DNA
  • CA9 protein, human
  • Carbonic Anhydrase IX
  • Carbonic Anhydrases