title: Evaluation of substituted 6-arylquinazolin-4-amines as potent and selective inhibitors of cdc2-like kinases (Clk).
abstract: A series of substituted 6-arylquinazolin-4-amines were prepared and analyzed as inhibitors of Clk4. Synthesis, structure-activity relationships and the selectivity of a potent analogue against a panel of 402 kinases are presented. Inhibition of Clk4 by these agents at varied concentrations of assay substrates (ATP and receptor peptide) highly suggests that this chemotype is an ATP competitive inhibitor. Molecular docking provides further evidence that inhibition is the result of binding at the kinase hinge region. Selected compounds represent novel tools capable of potent and selective inhibition of Clk1, Clk4, and Dyrk1A.
authors.affiliation: NIH Chemical Genomics Center, National Human Genome Research Institute, Bethesda, MD 20892-3370, USA.
authors.forename: Bryan T
authors.initials: BT
authors.lastname: Mott
authors.forename: Cordelle
authors.initials: C
authors.lastname: Tanega
authors.forename: Min
authors.initials: M
authors.lastname: Shen
authors.forename: David J
authors.initials: DJ
authors.lastname: Maloney
authors.forename: Paul
authors.initials: P
authors.lastname: Shinn
authors.forename: William
authors.initials: W
authors.lastname: Leister
authors.forename: Juan J
authors.initials: JJ
authors.lastname: Marugan
authors.forename: James
authors.initials: J
authors.lastname: Inglese
authors.forename: Christopher P
authors.initials: CP
authors.lastname: Austin
authors.forename: Tom
authors.initials: T
authors.lastname: Misteli
authors.forename: Douglas S
authors.initials: DS
authors.lastname: Auld
authors.forename: Craig J
authors.initials: CJ
authors.lastname: Thomas
mesh_terms: D000588:Amines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D018360:Crystallography, X-Ray; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D008958:Models, Molecular; D015394:Molecular Structure; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D011799:Quinazolines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D000588:Amines; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; C066780:Clk dual-specificity kinases; D011505:Protein-Tyrosine Kinases; D017346:Protein Serine-Threonine Kinases