title: Discovery of pyrido[3,4-g]quinazoline derivatives as CMGC family protein kinase inhibitors: Design, synthesis, inhibitory potency and X-ray co-crystal structure.
abstract: 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.
authors.affiliation: Université Clermont Auvergne, Université Blaise Pascal, Institut de Chimie de Clermont-Ferrand, BP 10448, F-63000 Clermont-Ferrand, France; CNRS, UMR 6296, ICCF, F-63178 Aubière, France.
authors.forename: Yannick J
authors.initials: YJ
authors.lastname: Esvan
authors.affiliation: Université Clermont Auvergne, Université Blaise Pascal, Institut de Chimie de Clermont-Ferrand, BP 10448, F-63000 Clermont-Ferrand, France; CNRS, UMR 6296, ICCF, F-63178 Aubière, France.
authors.forename: Wael
authors.initials: W
authors.lastname: Zeinyeh
authors.affiliation: Université Clermont Auvergne, Université Blaise Pascal, Institut de Chimie de Clermont-Ferrand, BP 10448, F-63000 Clermont-Ferrand, France; CNRS, UMR 6296, ICCF, F-63178 Aubière, France.
authors.forename: Thibaut
authors.initials: T
authors.lastname: Boibessot
authors.affiliation: Université Clermont Auvergne, Université Blaise Pascal, Institut de Chimie de Clermont-Ferrand, BP 10448, F-63000 Clermont-Ferrand, France; CNRS, UMR 6296, ICCF, F-63178 Aubière, France.
authors.forename: Lionel
authors.initials: L
authors.lastname: Nauton
authors.affiliation: Université Clermont Auvergne, Université Blaise Pascal, Institut de Chimie de Clermont-Ferrand, BP 10448, F-63000 Clermont-Ferrand, France; CNRS, UMR 6296, ICCF, F-63178 Aubière, France.
authors.forename: Vincent
authors.initials: V
authors.lastname: Théry
authors.affiliation: Structural Genomics Consortium, University of Oxford, Old Road Campus Building, Roosevelt Drive, Oxford OX3 7DQ, UK; Department of Clinical Pharmacology, University of Oxford, Old Road Campus Building, Roosevelt Drive, Oxford OX3 7DQ, UK.
authors.forename: Stefan
authors.initials: S
authors.lastname: Knapp
authors.affiliation: Structural Genomics Consortium, University of Oxford, Old Road Campus Building, Roosevelt Drive, Oxford OX3 7DQ, UK; Department of Clinical Pharmacology, University of Oxford, Old Road Campus Building, Roosevelt Drive, Oxford OX3 7DQ, UK.
authors.forename: Apirat
authors.initials: A
authors.lastname: Chaikuad
authors.affiliation: ManRos Therapeutics, Centre de Perharidy, 29680 Roscoff, France.
authors.forename: Nadège
authors.initials: N
authors.lastname: Loaëc
authors.affiliation: ManRos Therapeutics, Centre de Perharidy, 29680 Roscoff, France.
authors.forename: Laurent
authors.initials: L
authors.lastname: Meijer
authors.affiliation: Université Clermont Auvergne, Université Blaise Pascal, Institut de Chimie de Clermont-Ferrand, BP 10448, F-63000 Clermont-Ferrand, France; CNRS, UMR 6296, ICCF, F-63178 Aubière, France.
authors.forename: Fabrice
authors.initials: F
authors.lastname: Anizon
authors.affiliation: Université Clermont Auvergne, Université Blaise Pascal, Institut de Chimie de Clermont-Ferrand, BP 10448, F-63000 Clermont-Ferrand, France; CNRS, UMR 6296, ICCF, F-63178 Aubière, France. Electronic address: Francis.GIRAUD@univ-bpclermont.fr.
authors.forename: Francis
authors.initials: F
authors.lastname: Giraud
authors.affiliation: Université Clermont Auvergne, Université Blaise Pascal, Institut de Chimie de Clermont-Ferrand, BP 10448, F-63000 Clermont-Ferrand, France; CNRS, UMR 6296, ICCF, F-63178 Aubière, France. Electronic address: Pascale.MOREAU@univ-bpclermont.fr.
authors.forename: Pascale
authors.initials: P
authors.lastname: Moreau
mesh_terms: D000595:Amino Acid Sequence; D060326:Chemistry Techniques, Synthetic; D018360:Crystallography, X-Ray; D015195:Drug Design; D006801:Humans; D008958:Models, Molecular; D011487:Protein Conformation; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D011799:Quinazolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D017346:Protein Serine-Threonine Kinases
keywords: CLK1 binding mode; CMGC family; Kinase inhibitors; Pyrido[3,4-g]quinazoline; Ser/Thr kinases