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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
Article, Secondary publication

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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.

Item Type: Article
Erschienen: 2019
Creators: Bensinger, Dennis ; Stubba, Daniel ; Cremer, Anjali ; Kohl, Vanessa ; Waßmer, Theresa ; Stuckert, Johanna ; Engemann, Victoria ; Stegmaier, Kimberly ; Schmitz, Katja ; Schmidt, Boris
Type of entry: Secondary publication
Title: Virtual Screening Identifies Irreversible FMS-like Tyrosine Kinase 3 Inhibitors with Activity toward Resistance-Conferring Mutations
Language: English
Date: 2019
Place of Publication: Darmstadt
Year of primary publication: 2019
Publisher: American Chemical Society
Journal or Publication Title: Journal of Medicinal Chemistry
Volume of the journal: 62
Issue Number: 5
DOI: 10.25534/tuprints-00009651
URL / URN: https://tuprints.ulb.tu-darmstadt.de/9651
Corresponding Links:
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
Classification DDC: 500 Science and mathematics > 540 Chemistry
Divisions: 07 Department of Chemistry
07 Department of Chemistry > Clemens-Schöpf-Institut > Fachgebiet Biochemie
07 Department of Chemistry > Clemens-Schöpf-Institut
07 Department of Chemistry > Clemens-Schöpf-Institut > Organ Chemistry
Date Deposited: 08 Dec 2019 20:55
Last Modified: 11 Apr 2024 11:29
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