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

• Published in: European journal of medicinal chemistry Vol. 215; p. 113299
• Main Authors: Němec, Václav, Maier, Lukáš, Berger, Benedict-Tilman, Chaikuad, Apirat, Drápela, Stanislav, Souček, Karel, Knapp, Stefan, Paruch, Kamil
• Format: Journal Article
• Language: English
• Published: ISSY-LES-MOULINEAUX Elsevier Masson SAS 05.04.2021; Elsevier
• Subjects: Chemistry, Medicinal; CLK; Furo[3,2-b]pyridine; HIPK; Inhibitor; Kinase; Life Sciences & Biomedicine; MU1210; MU135; MU1787; Pharmacology & Pharmacy; Science & Technology; MU1210; CLK; Furo[3,2-b]pyridine; Kinase; MU1787; Inhibitor; HIPK; MU135; REGULATOR; IMPACT; DISCOVERY
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2021.113299

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. chemical biology probe [Display omitted] •The CLK probe MU1210 can be prepared in 6 steps from easily available precursors.•The furo [3,2-b]pyridine scaffold is the basis of highly selective HIPK inhibitors.•Crystal structure of the selective inhibitor MU135 in HIPK2 reveals the binding mode.