title: Novel CLK1 inhibitors based on N-aryloxazol-2-amine skeleton - A possible way to dual VEGFR2 TK/CLK ligands.
abstract: BACKGROUND
  Inhibitors of CLK protein kinases suppress cell growth and induce apoptosis by modulating pre-mRNA splicing in cancer. CLK family kinases are also involved in alternative splicing and RNA processing in Duchenne muscular dystrophy, Alzheimer's disease, HIV-1, and influenza virus. Small inhibitors are valuable tools for better understanding the molecular mechanisms of splicing and may serve as seeds for a novel class of therapeutics.
  
  
  RESULTS
  Here we describe a discovery of four novel CLK1 inhibitors possessing N-aryloxazol-2-amine skeleton. Their activity against CLK1 (IC50: 20, 30, 40 and 80 nM) and some other CMGC kinases, predicted CLK binding poses, synthesis and physico-chemical characteristics are also stated. Additionally analysis of all PDB available CLK structures and interactions of their ligands was performed. There are only few powerful dual CLK/VEGFR inhibitors known in the literature. We proposed that our inhibitors have similar binding places and interactions in CLK1, 3 and VEGFR2 TK mostly due to the joint N-aryloxazol-2-amine pharmacophoric fragment. One of our N-aryloxazol-2-amines already proved a good activity against both VEGFR2 and CLK1 enzymes (23/80 nM, resp). We proposed that the presented class of compounds has a potential to be developed in dual VEGFR2/CLK clinical compounds with prospective synergy to treat cancer.
authors.affiliation: Department of Organic Chemistry, Faculty of Natural Sciences, Comenius University in Bratislava, Mlynská Dolina, Ilkovičova 6, 842 15 Bratislava, Slovakia.
authors.forename: Miroslav
authors.initials: M
authors.lastname: Murár
authors.affiliation: Department of Organic Chemistry, Faculty of Natural Sciences, Comenius University in Bratislava, Mlynská Dolina, Ilkovičova 6, 842 15 Bratislava, Slovakia.
authors.forename: Juraj
authors.initials: J
authors.lastname: Dobiaš
authors.affiliation: Department of Organic Chemistry, Faculty of Natural Sciences, Comenius University in Bratislava, Mlynská Dolina, Ilkovičova 6, 842 15 Bratislava, Slovakia; Université de Strasbourg, Ecole Européenne de Chimie, Polyméres et Matériaux (ECPM) Laboratoire de Synthése et Catalyse (UMR CNRS 7509), 25, Rue Becquerel, F-67087 Strasbourg, France.
authors.forename: Peter
authors.initials: P
authors.lastname: Šramel
authors.affiliation: Institute of Chemistry, Faculty of Natural Sciences, Comenius University in Bratislava, Mlynská Dolina, Ilkovičova 6, 842 15 Bratislava, Slovakia.
authors.forename: Gabriela
authors.initials: G
authors.lastname: Addová
authors.affiliation: Université de Strasbourg, Ecole Européenne de Chimie, Polyméres et Matériaux (ECPM) Laboratoire de Synthése et Catalyse (UMR CNRS 7509), 25, Rue Becquerel, F-67087 Strasbourg, France.
authors.forename: Gilles
authors.initials: G
authors.lastname: Hanquet
authors.affiliation: Department of Organic Chemistry, Faculty of Natural Sciences, Comenius University in Bratislava, Mlynská Dolina, Ilkovičova 6, 842 15 Bratislava, Slovakia; Biomagi, Ltd., Mamateyova 26, 851 04 Bratislava, Slovakia. Electronic address: andrej.bohac@fns.uniba.sk.
authors.forename: Andrej
authors.initials: A
authors.lastname: Boháč
mesh_terms: D017398:Alternative Splicing / Q000187:drug effects; D000588:Amines / Q000737:chemistry / Q000494:pharmacology; D001665:Binding Sites; D055808:Drug Discovery; D006801:Humans; D008024:Ligands; D010080:Oxazoles / Q000737:chemistry* / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors*
chemical_list: D000588:Amines; D008024:Ligands; D010080:Oxazoles; D047428:Protein Kinase Inhibitors; C066780:Clk dual-specificity kinases; C000588866:KDR protein, human; D011505:Protein-Tyrosine Kinases; D040301:Vascular Endothelial Growth Factor Receptor-2; D017346:Protein Serine-Threonine Kinases
keywords: CDK9; DYRK1A; Dual CLK1/VEGFR2 kinase ligands; GSK3; GSK3α/β; IPHOJHHAZPKUQW-UHFFFAOYSA-N; Muti-targeted kinase inhibitors; XQSZOOXIJIGDLV-UHFFFAOYSA-N; YIEXHVPVWYOPCC-MDZDMXLPSA-N; ZIKVYDDNZDVYHF-UHFFFAOYSA-N