Stereo- and regiodefined DNA-encoded chemical libraries enable efficient tumour-targeting applications

  • Nat Chem. 2021 Jun;13(6):540-548. doi: 10.1038/s41557-021-00660-y.
Nicholas Favalli  1 ,  Gabriele Bassi  1 ,  Christian Pellegrino  1 ,  Jacopo Millul  2 ,  Roberto De Luca  2 ,  Samuele Cazzamalli  2 ,  Su Yang  3 ,  Anika Trenner  4 ,  Nour L Mozaffari  4 ,  Renier Myburgh  5 ,  Mustafa Moroglu  6 ,  Stuart J Conway  6 ,  Alessandro A Sartori  4 ,  Markus G Manz  5 ,  Richard A Lerner  7 ,  Peter K Vogt  3 ,  Jörg Scheuermann  8 ,  Dario Neri  9
Affiliations
  • 1. Department of Chemistry and Applied Biosciences, Swiss Federal Institute of Technology (ETH Zurich), Zurich, Switzerland.
  • 2. Philochem AG, Otelfingen, Switzerland.
  • 3. Department of Molecular Medicine, Scripps Research Institute, La Jolla, CA, USA.
  • 4. Institute of Molecular Cancer Research, University of Zurich, Zurich, Switzerland.
  • 5. Department of Medical Oncology and Hematology, University Hospital Zurich and University of Zurich, Comprehensive Cancer Center Zurich (CCCZ), Zurich, Switzerland.
  • 6. Department of Chemistry, Chemistry Research Laboratory, University of Oxford, Oxford, UK.
  • 7. Department of Chemistry, Scripps Research Institute, La Jolla, CA, USA.
  • 8. Department of Chemistry and Applied Biosciences, Swiss Federal Institute of Technology (ETH Zurich), Zurich, Switzerland. [email protected].
  • 9. Department of Chemistry and Applied Biosciences, Swiss Federal Institute of Technology (ETH Zurich), Zurich, Switzerland. [email protected].
PMID: 33833446 DOI: 10.1038/s41557-021-00660-y
Abstract

The encoding of chemical compounds with amplifiable DNA tags facilitates the discovery of small-molecule ligands for proteins. To investigate the impact of stereo- and regiochemistry on ligand discovery, we synthesized a DNA-encoded library of 670,752 derivatives based on 2-azido-3-iodophenylpropionic acids. The library was selected against multiple proteins and yielded specific ligands. The selection fingerprints obtained for a set of protein targets of pharmaceutical relevance clearly showed the preferential enrichment of ortho-, meta- or para-regioisomers, which was experimentally verified by affinity measurements in the absence of DNA. The discovered ligands included novel selective enzyme inhibitors and Binders to tumour-associated Antigens, which enabled conditional chimeric antigen receptor T-cell activation and tumour targeting.

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