Furo[3,2-b]pyridine – a novel privileged scaffold for selective kinase inhibitors and effective
                                modulators of the Hedgehog pathway


  Václav Němec^a,b, Michaela Hylsová^a,b, Lukáš Maier^a,b, Jana Flegel^c, Sonja Sievers^c, Slava
 Ziegler^c, Martin Schroeder^d, Benedict-Tilman Berger^d, Apirat Chaikuad^d, Barbora Valčíková^e,
  Stjepan Uldrijan^e, Stanislav Drápel^af, Karel Souček^f, Herbert Waldmann^c, Stefan Knapp^d and
                                        Kamil Paruch^a,b,*


   ^aDepartment of Chemistry, CZ-OPENSCREEN, Masaryk University, Kamenice 5, 625 00 Brno, Czech
                                             Republic.

^bInternational Clinical Research Center, St. Anne’s University Hospital Brno, Pekařská 53, 656 91
                                       Brno, Czech Republic.

^cMax-Planck-Institute für Molekulare Physiologie, Abteiulung Chemische Biologie, Otto-Hahn-Strasse
  11, Dortmund, 44227, Germany. ^dInstitute for Pharmaceutical Chemistry, Structural Genomics and
            Consortium, Johann Wolfgang Goethe-University, Frankfurt am Main, Germany.

 ^eDepartment of Biology, Faculty of Medicine, Masaryk University, Kamenice 5, Brno, 625 00, Czech
                                             Republic.

 ^fDepartment of Cytokinetics, Institute of Biophysics CAS, Královopolská 135, Brno, 612 65, Czech
                                             Republic.

                                      ^*paruch@chemi.muni.cz


Abstract

We report the identification of the furo[3,2-b]pyridine (FP) 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 via 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 non-toxic modulators of the Hedgehog pathway.



Acknowledgements


The work was supported by the following grants: CZ-OPENSCREEN: National Infrastructure for Chemical
Biology (Identification code: LM2015063), Preclinical Progression of New Organic Compounds with
Targeted Biological Activity (CZ CZ.02.1.01/0.0/0.0/16_025/0007381), MUNI/E/0456/2018, and the
National Program of Sustainability II (MEYS CR, project No. LQ1605). A-T.B, MS, AC and SK are
grateful for support by the SGC, a registered charity (number 1097737).