2. Academic Validation
  3. Stereo- and regiodefined DNA-encoded chemical libraries enable efficient tumour-targeting applications

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

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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