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Virtual Screening Identifies Irreversible FMS-like Tyrosine Kinase 3 Inhibitors with Activity toward Resistance-Conferring Mutations

Bensinger, Dennis ; Stubba, Daniel ; Cremer, Anjali ; Kohl, Vanessa ; Waßmer, Theresa ; Stuckert, Johanna ; Engemann, Victoria ; Stegmaier, Kimberly ; Schmitz, Katja ; Schmidt, Boris (2019)
Virtual Screening Identifies Irreversible FMS-like Tyrosine Kinase 3 Inhibitors with Activity toward Resistance-Conferring Mutations.
In: Journal of Medicinal Chemistry, 2019, 62 (5)
doi: 10.25534/tuprints-00009651
Artikel, Zweitveröffentlichung

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Kurzbeschreibung (Abstract)

The use of covalent irreversible binding inhibitors is an established concept for drug development. Usually, the discovery of new irreversible kinase inhibitors occurs serendipitously, showing that efficient rational approaches for the rapid discovery of new drugs are needed. Herein, we report a virtual screening strategy that led to the discovery of irreversible inhibitors of FMS-like tyrosine kinase 3 (FLT3) involved in the pathogenesis of acute myeloid leukemia. A virtual screening library was designed to target the highly conserved Cys828 residue preceding the DFG motif by modification of reported reversible inhibitors with chemically reactive groups. Prospective covalent docking allowed the identification of two lead series, resulting in a massive increase in inhibition of kinase activity and cell viability by irreversible inhibitors compared to the corresponding reversible scaffolds. Lead compound 4b (BSc5371) displays superior cytotoxicity in FLT3-dependent cell lines to compounds in recent clinical trials and overcomes drug-resistant mutations.

Typ des Eintrags: Artikel
Erschienen: 2019
Autor(en): Bensinger, Dennis ; Stubba, Daniel ; Cremer, Anjali ; Kohl, Vanessa ; Waßmer, Theresa ; Stuckert, Johanna ; Engemann, Victoria ; Stegmaier, Kimberly ; Schmitz, Katja ; Schmidt, Boris
Art des Eintrags: Zweitveröffentlichung
Titel: Virtual Screening Identifies Irreversible FMS-like Tyrosine Kinase 3 Inhibitors with Activity toward Resistance-Conferring Mutations
Sprache: Englisch
Publikationsjahr: 2019
Ort: Darmstadt
Publikationsdatum der Erstveröffentlichung: 2019
Verlag: American Chemical Society
Titel der Zeitschrift, Zeitung oder Schriftenreihe: Journal of Medicinal Chemistry
Jahrgang/Volume einer Zeitschrift: 62
(Heft-)Nummer: 5
DOI: 10.25534/tuprints-00009651
URL / URN: https://tuprints.ulb.tu-darmstadt.de/9651
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Kurzbeschreibung (Abstract):

The use of covalent irreversible binding inhibitors is an established concept for drug development. Usually, the discovery of new irreversible kinase inhibitors occurs serendipitously, showing that efficient rational approaches for the rapid discovery of new drugs are needed. Herein, we report a virtual screening strategy that led to the discovery of irreversible inhibitors of FMS-like tyrosine kinase 3 (FLT3) involved in the pathogenesis of acute myeloid leukemia. A virtual screening library was designed to target the highly conserved Cys828 residue preceding the DFG motif by modification of reported reversible inhibitors with chemically reactive groups. Prospective covalent docking allowed the identification of two lead series, resulting in a massive increase in inhibition of kinase activity and cell viability by irreversible inhibitors compared to the corresponding reversible scaffolds. Lead compound 4b (BSc5371) displays superior cytotoxicity in FLT3-dependent cell lines to compounds in recent clinical trials and overcomes drug-resistant mutations.

URN: urn:nbn:de:tuda-tuprints-96515
Sachgruppe der Dewey Dezimalklassifikatin (DDC): 500 Naturwissenschaften und Mathematik > 540 Chemie
Fachbereich(e)/-gebiet(e): 07 Fachbereich Chemie
07 Fachbereich Chemie > Clemens-Schöpf-Institut > Fachgebiet Biochemie
07 Fachbereich Chemie > Clemens-Schöpf-Institut
07 Fachbereich Chemie > Clemens-Schöpf-Institut > Fachgebiet Organische Chemie
Hinterlegungsdatum: 08 Dez 2019 20:55
Letzte Änderung: 11 Apr 2024 11:29
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