title: Identification and further development of potent TBK1 inhibitors.
abstract: The cytosolic Ser/Thr kinase TBK1 was discovered to be an essential element in the mediation of signals that lead to tumor migration and progression. These findings meet the need for the identification of novel tool compounds and potential therapeutics to gain deeper insights into TBK1 related signaling and its relevance in tumor progression. Herein, we undertake the activity-based screening for unique inhibitors of TBK1 and their subsequent optimization. Initial screening approaches identified a selection of TBK1 inhibitors that were optimized using methods of medicinal chemistry. Variations of the structural characteristics of a representative 2,4,6-substituted pyrimidine scaffold resulted in improved potency. Prospective use as tool compounds or basic contributions to drug design approaches are anticipated for our improved small molecules.
authors.affiliation: Department of Chemistry and Chemical Biology, Technical University of Dortmund , Otto-Hahn-Straße 6, 44227 Dortmund, Germany.
authors.forename: André
authors.initials: A
authors.lastname: Richters
authors.forename: Debjit
authors.initials: D
authors.lastname: Basu
authors.forename: Julian
authors.initials: J
authors.lastname: Engel
authors.forename: Meryem S
authors.initials: MS
authors.lastname: Ercanoglu
authors.forename: Hyatt
authors.initials: H
authors.lastname: Balke-Want
authors.forename: Roberta
authors.initials: R
authors.lastname: Tesch
authors.forename: Roman K
authors.initials: RK
authors.lastname: Thomas
authors.forename: Daniel
authors.initials: D
authors.lastname: Rauh
mesh_terms: D000818:Animals; D002460:Cell Line; D015195:Drug Design; D006801:Humans; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D062105:Molecular Docking Simulation; D015394:Molecular Structure; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D054852:Small Molecule Libraries / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D047428:Protein Kinase Inhibitors; D054852:Small Molecule Libraries; C498588:Tbk1 protein, mouse; D017346:Protein Serine-Threonine Kinases; C403191:TBK1 protein, human