2. Academic Validation
  3. Furo[3,2-b]pyridine: A Privileged Scaffold for Highly Selective Kinase Inhibitors and Effective Modulators of the Hedgehog Pathway

Furo[3,2-b]pyridine: A Privileged Scaffold for Highly Selective Kinase Inhibitors and Effective Modulators of the Hedgehog Pathway

  • Angew Chem Int Ed Engl. 2019 Jan 21;58(4):1062-1066. doi: 10.1002/anie.201810312.
Václav Němec 1 2,  Michaela Hylsová 1 2,  Lukáš Maier 1 2,  Jana Flegel 3,  Sonja Sievers 3,  Slava Ziegler 3,  Martin Schröder 4,  Benedict-Tilman Berger 4,  Apirat Chaikuad 4,  Barbora Valčíková 2 5,  Stjepan Uldrijan 2 5,  Stanislav Drápela 2 6,  Karel Souček 2 6,  Herbert Waldmann 3,  Stefan Knapp 4,  Kamil Paruch 1 2
Affiliations

Affiliations

  • 1 Department of Chemistry, CZ-Openscreen, 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 Max-Planck-Institute für Molekulare Physiologie, Abteilung Chemische Biologie, Otto-Hahn-Strasse 11, 44227, Dortmund, Germany.
  • 4 Institute for Pharmaceutical Chemistry, Structural Genomics Consortium, Johann Wolfgang Goethe-University, Max-von-Laue-Strasse 15, 60438, Frankfurt am Main, Germany.
  • 5 Department of Biology, Faculty of Medicine, Masaryk University, Kamenice 5, Brno, 625 00, Czech Republic.
  • 6 Department of Cytokinetics, Institute of Biophysics CAS, Královopolská 135, Brno, 612 65, Czech Republic.
PMID: 30569600 DOI: 10.1002/anie.201810312
Abstract

Reported is the identification of the furo[3,2-b]pyridine core as a novel scaffold for potent and highly selective inhibitors of cdc-like kinases (CLKs) and efficient modulators of the Hedgehog signaling pathway. Initially, a diverse target compound set was prepared by synthetic sequences based on chemoselective metal-mediated couplings, including assembly of the furo[3,2-b]pyridine scaffold by copper-mediated oxidative cyclization. Optimization of the subseries containing 3,5-disubstituted furo[3,2-b]pyridines afforded potent, cell-active, and highly selective inhibitors of CLKs. Profiling of the kinase-inactive subset of 3,5,7-trisubstituted furo[3,2-b]pyridines revealed sub-micromolar modulators of the Hedgehog pathway.

Keywords

biological activity; chemical probes; heterocycles; inhibitors; kinases.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-125290
    Inhibitor of CDC-like kinases