2. Academic Validation
  3. Design, Synthesis, and Biological Evaluation of 2-Hydroxy-4-phenylthiophene-3-carbonitrile as PD-L1 Antagonist and Its Comparison to Available Small Molecular PD-L1 Inhibitors

Design, Synthesis, and Biological Evaluation of 2-Hydroxy-4-phenylthiophene-3-carbonitrile as PD-L1 Antagonist and Its Comparison to Available Small Molecular PD-L1 Inhibitors

  • J Med Chem. 2023 Jul 27;66(14):9577-9591. doi: 10.1021/acs.jmedchem.3c00254.
Marta A Ważyńska 1,  Roberto Butera 2,  Marta Requesens 1,  Annechien Plat 1,  Tryfon Zarganes-Tzitzikas 3,  Constantinos G Neochoritis 4,  Jacek Plewka 5,  Lukasz Skalniak 5,  Justyna Kocik-Krol 5 6,  Bogdan Musielak 5,  Katarzyna Magiera-Mularz 5,  Ismael Rodriguez 5 6,  Simon N Blok 7,  Marco de Bruyn 1,  Hans W Nijman 1,  Philip H Elsinga 7,  Tad A Holak 5,  Alexander Dömling 2 8
Affiliations

Affiliations

  • 1 Department of Obstetrics and Gynecology, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9713 GZ Groningen, The Netherlands.
  • 2 Department of Drug Design, University of Groningen, A. Deusinglaan 1, 9713 AV Groningen, The Netherlands.
  • 3 Centre for Medicines Discovery, Nuffield Department of Medicine, Alzheimer's Research UK Oxford Drug Discovery Institute, NDM Research Building, Roosevelt Drive, OX3 7FZ Oxford, U.K.
  • 4 Department of Chemistry, University of Crete, Voutes, 70013 Heraklion, Greece.
  • 5 Department of Organic Chemistry, Faculty of Chemistry, Jagiellonian University, Gronostajowa 2, 30-387 Krakow, Poland.
  • 6 Doctoral School of Exact and Natural Sciences, Jagiellonian University, Prof. St. Łojasiewicz St 11, 30-348 Krakow, Poland.
  • 7 Department of Nuclear Medicine and MolecularImaging, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9713 GZ Groningen, The Netherlands.
  • 8 Institute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry and Czech Advanced Technology and Research Institute, Palacky University in Olomouc, Olomouc 77900, Czech Republic.
PMID: 37450644 DOI: 10.1021/acs.jmedchem.3c00254
Abstract

In search of a potent small molecular PD-L1 inhibitor, we designed and synthesized a compound based on a 2-hydroxy-4-phenylthiophene-3-carbonitrile moiety. Ligand's performance was tested in vitro and compared side-by-side with a known PD-L1 antagonist with a proven bioactivity BMS1166. Subsequently, we modified both compounds to allow 18F labeling that could be used for PET imaging. Radiolabeling, which is used in drug development and diagnosis, was applied to investigate the properties of those ligands and test them against tissue sections with diverse expression levels of PD-L1. We confirmed biological activity toward hPD-L1 for this inhibitor, comparable with BMS1166, while holding enhanced pharmacological properties.

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