Discovery of pyrido[3,4-g]quinazoline derivatives as CMGC family protein kinase inhibitors: Design, synthesis, inhibitory potency and X-ray co–crystal structure

• DOI: 10.1016/j.ejmech.2016.04.004
• Publication Date: 2016-04-05T08:52:59Z
• Authors: Yannick J. Esvan; Wael Zeinyeh; Thibaut Boibessot; Lionel Nauton; Vincent Théry; Stefan Knapp; Apirat Chaikuad; Nadège Loaëc; Laurent Meijer; Fabrice Anizon; Francis Giraud; Pascale Moreau
• Keywords: Models, Molecular; 0301 basic medicine; CMGC family; Protein Conformation; 4-g]quinazoline; Chemistry Techniques, Synthetic; Protein Serine-Threonine Kinases; Pyrido[3; Crystallography, X-Ray; CLK1 binding mode; Structure-Activity Relationship; 03 medical and health sciences; Kinase inhibitors; Drug Design; Quinazolines; [CHIM]Chemical Sciences; Humans; Amino Acid Sequence; Ser/Thr kinases; Protein Kinase Inhibitors

The design and synthesis of new pyrido[3,4-g]quinazoline derivatives is described as well as their protein kinase inhibitory potencies toward five CMGC family members (CDK5, CK1, GSK3, CLK1 and DYRK1A). The interest for this original tricyclic heteroaromatic scaffold as modulators of CLK1/DYRK1A activity was validated by nanomolar potencies (compounds 12 and 13). CLK1 co-crystal structures with two inhibitors revealed the binding mode of these compounds within the ATP-binding pocket.