title: Modification of a promiscuous inhibitor shifts the inhibition from γ-secretase to FLT-3.
abstract: The inhibition of FLT-3 activity is an interesting target for the treatment of acute myeloid leukemia (AML). The serendipitous identification of FLT-3 inhibitors from a CK1/γ-secretase programme provided compounds with dual inhibitory activity. We analyzed the structure-activity relationship of these inhibitors and derivatized them to arrive at compounds with reduced impact on γ-secretase activity and enhanced FLT-3 inhibition.
authors.affiliation: Clemens Schöpf-Institute of Organic Chemistry and Biochemistry, Technische Universität Darmstadt, Petersenstr. 22, D-64287 Darmstadt, Germany.
authors.forename: Ghislaine Marlyse Okala
authors.initials: GM
authors.lastname: Amombo
authors.forename: Thomas
authors.initials: T
authors.lastname: Kramer
authors.forename: Fabio
authors.initials: F
authors.lastname: Lo Monte
authors.forename: Stefan
authors.initials: S
authors.lastname: Göring
authors.forename: Matthias
authors.initials: M
authors.lastname: Fach
authors.forename: Steven
authors.initials: S
authors.lastname: Smith
authors.forename: Stephanie
authors.initials: S
authors.lastname: Kolb
authors.forename: Robert
authors.initials: R
authors.lastname: Schubenel
authors.forename: Karlheinz
authors.initials: K
authors.lastname: Baumann
authors.forename: Boris
authors.initials: B
authors.lastname: Schmidt
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000818:Animals; D004305:Dose-Response Relationship, Drug; D004625:Embryo, Nonmammalian / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D015394:Molecular Structure; D010641:Phenotype; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D013329:Structure-Activity Relationship; D013379:Substrate Specificity; D015027:Zebrafish / Q000196:embryology; D051941:fms-Like Tyrosine Kinase 3 / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; D011994:Recombinant Proteins; C497970:FLT3 protein, human; D051941:fms-Like Tyrosine Kinase 3; D053829:Amyloid Precursor Protein Secretases