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 |
| Zugehörige Links: | |
| 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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| Suche nach Titel in: | TUfind oder in Google |
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- Virtual Screening Identifies Irreversible FMS-like Tyrosine Kinase 3 Inhibitors with Activity toward Resistance-Conferring Mutations. (deposited 08 Dez 2019 20:55) [Gegenwärtig angezeigt]
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