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Furo[3,2- b ]pyridine: A privileged scaffold for highly selective kinase inhibitors and effective modulators of the Hedgehog pathway

DOI: 10.1002/anie.201810312 DOI Help

Authors: Václav Němec (Masaryk University; St. Anne's University Hospital) , Michaela Hylsová (Masaryk University; St. Anne's University Hospital) , Lukáš Maier (Masaryk University; St. Anne's University Hospital) , Jana Flegel (Max-Planck-Institute fr Molekulare Physiologie) , Sonja Sievers (Max-Planck-Institute für Molekulare Physiologie) , Slava Ziegler (Max-Planck-Institute für Molekulare Physiologie) , Martin Schroeder (Structural Genomics Consortium, Johann Wolfgang Goethe-University) , Benedict-tilman Berger (Structural Genomics Consortium, Johann Wolfgang Goethe-University) , Apirat Chaikuad (Structural Genomics Consortium, Johann Wolfgang Goethe-University) , Barbora Valčíková (St. Anne's University Hospital; Masaryk University) , Stjepan Uldrijan (St. Anne's University Hospital; Masaryk University) , Stanislav Drápela (St. Anne's University Hospital; Institute of Biophysics CAS) , Karel Souček (St. Anne's University Hospital; Institute of Biophysics CAS) , Herbert Waldmann (Max-Planck-Institute für Molekulare Physiologie) , Stefan Knapp (Structural Genomics Consortium, Johann Wolfgang Goethe-University) , Kamil Paruch (Masaryk University; St. Anne's University Hospital)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Angewandte Chemie International Edition , VOL 10

State: Published (Approved)
Published: December 2018
Diamond Proposal Number(s): 10619

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.

Journal Keywords: biological activity; chemical probes; heterocycles; inhibitors; kinases

Subject Areas: Chemistry, Biology and Bio-materials, Medicine


Instruments: I02-Macromolecular Crystallography , I04-1-Macromolecular Crystallography (fixed wavelength)