title: Conformation-Selective Analogues of Dasatinib Reveal Insight into Kinase Inhibitor Binding and Selectivity.
abstract: In the kinase field, there are many widely held tenets about conformation-selective inhibitors that have yet to be validated using controlled experiments. We have designed, synthesized, and characterized a series of kinase inhibitor analogues of dasatinib, an FDA-approved kinase inhibitor that binds the active conformation. This inhibitor series includes two Type II inhibitors that bind the DFG-out inactive conformation and two inhibitors that bind the αC-helix-out inactive conformation. Using this series of compounds, we analyze the impact that conformation-selective inhibitors have on target binding and kinome-wide selectivity.
authors.forename: Frank E
authors.initials: FE
authors.lastname: Kwarcinski
authors.forename: Kristoffer R
authors.initials: KR
authors.lastname: Brandvold
authors.forename: Sameer
authors.initials: S
authors.lastname: Phadke
authors.forename: Omar M
authors.initials: OM
authors.lastname: Beleh
authors.forename: Taylor K
authors.initials: TK
authors.lastname: Johnson
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Meagher
authors.affiliation: Department of Pharmacological Sciences, Stony Brook University , Stony Brook, New York 11794, United States.
authors.forename: Markus A
authors.initials: MA
authors.lastname: Seeliger
authors.forename: Jeanne A
authors.initials: JA
authors.lastname: Stuckey
authors.forename: Matthew B
authors.initials: MB
authors.lastname: Soellner
mesh_terms: D000818:Animals; D002645:Chickens; D000069439:Dasatinib / Q000031:analogs & derivatives* / Q000494:pharmacology*; D015195:Drug Design; D006801:Humans; D062105:Molecular Docking Simulation; D011485:Protein Binding; D011487:Protein Conformation; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D011494:Protein Kinases / Q000737:chemistry / Q000378:metabolism*
chemical_list: D047428:Protein Kinase Inhibitors; D011494:Protein Kinases; D000069439:Dasatinib