Highly selective inhibitors of protein kinases CLK and HIPK with the furo[3,2-b]pyridine core.

Abstract The furo[3,2-b]pyridine motif represents a relatively underexplored central pharmacophore in the area of kinase inhibitors. Herein, we report flexible synthesis of 3,5-disubstituted furo[3,2-b]pyridines that relies on chemoselective couplings of newly prepared 5-chloro-3-iodofuro[3,2-b]pyridine. This methodology allowed efficient second-generation synthesis of the state-of-the-art chemical biology probe for CLK1/2/4 MU1210, and identification of the highly selective inhibitors of HIPKs MU135 and MU1787 which are presented and characterized in this study, including the X-ray crystal structure of MU135 in HIPK2.