Discovery of New Protein Kinase Inhibitors with the Furo [3,2-b]pyridine Core



Václav Němec



Development of new protein kinase inhibitors has been a very active field in the academic as well
as in the industrial sector. Up to date, 30 compounds that are currently clinically used have been
identified. The central hypothesis of our project was that the furo[3,2-b]pyridine motif could
serve as a proper bioisostere of the pyrazolo[1,5-a]pyrimidine pharmacophore, which was
successfully used in numerous series of potent and selective inhibitors of various protein kinases.
Interestingly, only a few series of furo[3,2-b]pyridine-based protein kinase inhibitors were
documented in the (patent) literature. In addition, furo[3,2-b]pyridines with NHR substituents at
the 7 position, which are generally important for the interaction with the hinge regions of
kinases, were not known at all. In order to prepare the initial set of furo[3,2-b]pyridines with
particular substitutions patterns at positions 3, 5, 6 and 7, we optimized two known methods to
assemble the furo[3,2-b]pyridine core and developed one new annulation methodology. While some
direct analogs of known pyrazolo[1,5-a]pyrimidine inhibitors proved to be less potent, the series
with proper substituents at positions 3 and 5 of the furo[3,2-b]pyridine scaffold contained some
highly potent (IC[50] < 50 nM) and selective inhibitors of CLK and HIPK kinases, which emerged only
recently as possible therapeutic targets. Of note, the activities of the most potent compounds
would be hardly predictable from the available crystal structures - they would suggest that the
size of the ATP binding site’s cavity would be insufficient to accommodate some “most active”
substituents at position 3 of the core.