title: Benzobisthiazoles Represent a Novel Scaffold for Kinase Inhibitors of CLK Family Members.
abstract: Protein kinases are essential regulators of most cellular processes and are involved in the etiology and progression of multiple diseases. The cdc2-like kinases (CLKs) have been linked to various neurodegenerative disorders, metabolic regulation, and virus infection, and the kinases have been recognized as potential drug targets. Here, we have developed a screening workflow for the identification of potent CLK2 inhibitors and identified compounds with a novel chemical scaffold structure, the benzobisthiazoles, that has not been previously reported for kinase inhibitors. We propose models for binding of these compounds to CLK family proteins and key residues in CLK2 that are important for the compound interactions and the kinase activity. We identified structural elements within the benzobisthiazole that determine CLK2 and CLK3 inhibition, thus providing a rationale for selectivity assays. In summary, our results will inform structure-based design of CLK family inhibitors based on the novel benzobisthiazole scaffold.
authors.affiliation: MRC Laboratory for Molecular Cell Biology, University College London , London WC1E 6BT, U.K.
authors.forename: Krisna
authors.initials: K
authors.lastname: Prak
authors.affiliation: MRC Laboratory for Molecular Cell Biology, University College London , London WC1E 6BT, U.K.
authors.forename: Janos
authors.initials: J
authors.lastname: Kriston-Vizi
authors.affiliation: Wolfson Institute for Biomedical Research, University College London , London WC1E 6BT, U.K.
authors.forename: A W Edith
authors.initials: AW
authors.lastname: Chan
authors.affiliation: MRC Laboratory for Molecular Cell Biology, University College London , London WC1E 6BT, U.K.
authors.forename: Christin
authors.initials: C
authors.lastname: Luft
authors.affiliation: MRC Laboratory for Molecular Cell Biology, University College London , London WC1E 6BT, U.K.
authors.forename: Joana R
authors.initials: JR
authors.lastname: Costa
authors.affiliation: MRC Laboratory for Molecular Cell Biology, University College London , London WC1E 6BT, U.K.
authors.forename: Niccolo
authors.initials: N
authors.lastname: Pengo
authors.affiliation: MRC Laboratory for Molecular Cell Biology, University College London , London WC1E 6BT, U.K.
authors.forename: Robin
authors.initials: R
authors.lastname: Ketteler
mesh_terms: D000595:Amino Acid Sequence; D052160:Benzothiazoles / Q000138:chemical synthesis / Q000737:chemistry*; D006801:Humans; D062105:Molecular Docking Simulation; D008969:Molecular Sequence Data; D009154:Mutation; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics; D016415:Sequence Alignment; D054852:Small Molecule Libraries; D013329:Structure-Activity Relationship
chemical_list: D052160:Benzothiazoles; D054852:Small Molecule Libraries; C066780:Clk dual-specificity kinases; D011505:Protein-Tyrosine Kinases; D017346:Protein Serine-Threonine Kinases