title: Computer-guided design, synthesis, and biological evaluation of quinoxalinebisarylureas as FLT3 inhibitors.
abstract: Activating mutations of FMS-like tyrosine kinase 3 (FLT3) are present in ∼30 % of patients with acute myeloid leukemia (AML) and are associated with poor prognosis. Point mutations in the tyrosine kinase domain (TKD) are observed as primary mutations or are acquired as secondary mutations in FLT3 with internal tandem duplications (ITDs) after treatment with tyrosine kinase inhibitors (TKIs). Although dozens of potent inhibitors against FLT3 ITD have been reported, activating TKD point mutations, especially at residues F691 and D835, remain the leading cause for therapy resistance, highlighting the consistent need for new potent inhibitors. Herein we report the identification and characterization of novel quinoxaline-based FLT3 inhibitors. We used the pharmacophore features of diverse known inhibitors as a starting point for a new optimization algorithm for type II TKIs, starting from an in silico library pharmacophore search and induced-fit docking in the known FLT3 structure. This led to the design of a set of diverse quinoxalinebisarylureas, which were profiled in an FLT3 kinase activity assay. The most promising compounds were further evaluated in a zebrafish embryo phenotype assay.
authors: Clemens Schöpf-Institute of Organic Chemistry & Biochemistry, Technische Universität Darmstadt, 64287 Darmstadt (Germany).
authors: Stefan
authors: S
authors: Göring
authors: Dennis
authors: D
authors: Bensinger
authors: Eva C
authors: EC
authors: Naumann
authors: Boris
authors: B
authors: Schmidt
mesh_terms: D000818:Animals; D015195:Drug Design; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy / Q000201:enzymology; D062105:Molecular Docking Simulation; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D011810:Quinoxalines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D015027:Zebrafish; D051941:fms-Like Tyrosine Kinase 3 / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism
chemical_list: D047428:Protein Kinase Inhibitors; D011810:Quinoxalines; D051941:fms-Like Tyrosine Kinase 3
keywords: FMS-like tyrosine kinase 3; acute myeloid leukemia; drug discovery; inhibitors; zebrafish