title: Selectivity Profiling and Biological Activity of Novel β-Carbolines as Potent and Selective DYRK1 Kinase Inhibitors.
abstract: DYRK1A is a pleiotropic protein kinase with diverse functions in cellular regulation, including cell cycle control, neuronal differentiation, and synaptic transmission. Enhanced activity and overexpression of DYRK1A have been linked to altered brain development and function in Down syndrome and neurodegenerative diseases such as Alzheimer's disease. The β-carboline alkaloid harmine is a high affinity inhibitor of DYRK1A but suffers from the drawback of inhibiting monoamine oxidase A (MAO-A) with even higher potency. Here we characterized a series of novel harmine analogs with minimal or absent MAO-A inhibitory activity. We identified several inhibitors with submicromolar potencies for DYRK1A and selectivity for DYRK1A and DYRK1B over the related kinases DYRK2 and HIPK2. An optimized inhibitor, AnnH75, inhibited CLK1, CLK4, and haspin/GSG2 as the only off-targets in a panel of 300 protein kinases. In cellular assays, AnnH75 dose-dependently reduced the phosphorylation of three known DYRK1A substrates (SF3B1, SEPT4, and tau) without negative effects on cell viability. AnnH75 inhibited the cotranslational tyrosine autophosphorylation of DYRK1A and threonine phosphorylation of an exogenous substrate protein with similar potency. In conclusion, we have characterized an optimized β-carboline inhibitor as a highly selective chemical probe that complies with desirable properties of drug-like molecules and is suitable to interrogate the function of DYRK1A in biological studies.
authors.affiliation: Institute of Pharmacology and Toxicology, RWTH Aachen University, Aachen, Germany.
authors.forename: Katharina
authors.initials: K
authors.lastname: Rüben
authors.affiliation: Department of Pharmacy-Center for Drug Research, Ludwig Maximilian University, Munich, Germany.
authors.forename: Anne
authors.initials: A
authors.lastname: Wurzlbauer
authors.affiliation: Institute of Pharmacology and Toxicology, RWTH Aachen University, Aachen, Germany.
authors.forename: Agnes
authors.initials: A
authors.lastname: Walte
authors.affiliation: Institute of Pharmacy, Martin Luther University Halle-Wittenberg, Halle, Germany.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Sippl
authors.affiliation: Department of Pharmacy-Center for Drug Research, Ludwig Maximilian University, Munich, Germany.
authors.forename: Franz
authors.initials: F
authors.lastname: Bracher
authors.affiliation: Institute of Pharmacology and Toxicology, RWTH Aachen University, Aachen, Germany.
authors.forename: Walter
authors.initials: W
authors.lastname: Becker
mesh_terms: D000818:Animals; D002243:Carbolines / Q000494:pharmacology*; D006367:HeLa Cells; D006801:Humans; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D016716:PC12 Cells; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D051381:Rats; D000097603:Dyrk Kinases
chemical_list: D002243:Carbolines; D047428:Protein Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases; D011505:Protein-Tyrosine Kinases; D000097603:Dyrk Kinases