2. Academic Validation
  3. Thieno[3,2-b]pyridine: Attractive scaffold for highly selective inhibitors of underexplored protein kinases with variable binding mode

Thieno[3,2-b]pyridine: Attractive scaffold for highly selective inhibitors of underexplored protein kinases with variable binding mode

  • Angew Chem Int Ed Engl. 2025 Jan 2;64(1):e202412786. doi: 10.1002/anie.202412786.
Paula Martín Moyano 1 2,  Tadeáš Kubina 1,  Štěpán Owen Paruch 1,  Aneta Jarošková 3 4,  Jan Novotný 3 4,  Veronika Skočková 3,  Petra Ovesná 5,  Tereza Suchánková 3,  Polina Prokofeva 6,  Bernhard Kuster 6,  Michal Šmída 7,  Apirat Chaikuad 8,  Andreas Krämer 8,  Stefan Knapp 8,  Karel Souček 2 3 4,  Kamil Paruch 1 2
Affiliations

Affiliations

  • 1 Department of Chemistry, Faculty of Science, Masaryk University, Kamenice 5, Brno, 625 00, Czech Republic.
  • 2 International Clinical Research Centre, St. Anne's University Hospital, Pekařská 53, Brno, 656 91, Czech Republic.
  • 3 Institute of Biophysics, Czech Academy of Science, Královopolská 135, 612 00, Brno, Czech Republic.
  • 4 Department of Experimental Biology, Faculty of Science, Masaryk University, Kamenice 5, Brno, 625 00, Czech Republic.
  • 5 Institute of Biostatistics and Analyses, Masaryk University, Kamenice 5, Brno, 625 00, Czech Republic.
  • 6 Proteomics and Bioanalytics, Department of Molecular Life Sciences, School of Life Sciences, Technical University of Munich, Freising, 85354, Germany.
  • 7 CEITEC, Masaryk University, Kamenice 5, Brno, 625 00, Czech Republic.
  • 8 Institute for Pharmaceutical Chemistry, Structural Genomics Consortium, Johann Wolfgang Goethe-University, Max-von-Laue-Strasse 15, Frankfurt am Main, 60438, Germany.
PMID: 39503260 DOI: 10.1002/anie.202412786
Abstract

Protein kinases are key regulators of numerous biological processes and aberrant kinase activity can cause various diseases, particularly Cancer. Herein, we report the identification of new series of highly selective kinase inhibitors based on the thieno[3,2-b]pyridine scaffold. The weak interaction of the thieno[3,2-b]pyridine core with the kinase hinge region allows for profoundly different binding modes all of which maintain high kinome-wide selectivity, as illustrated by the isomers MU1464 and MU1668. Thus, this core structure provides a template of ATP-competitive but not ATP-mimetic inhibitors that are anchored at the kinase back pocket. Mapping the chemical space around the central thieno[3,2-b]pyridine pharmacophore afforded highly selective inhibitors of the kinase Haspin, exemplified by the compound MU1920 that fulfils criteria for a quality chemical probe and is suitable for use in in vivo applications. However, despite the role of Haspin in mitosis, the inhibition of Haspin alone was not sufficient to elicit cytotoxic effect in Cancer cells. The thieno[3,2-b]pyridine scaffold can be used in a broader context, as a basis of inhibitors targeting Other underexplored protein kinases, such as CDKLs.

Keywords

Haspin; chemical probe; kinase inhibitor; selectivity; thieno[3,2-b]pyridine.

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