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

Bensinger, Dennis and Stubba, Daniel and Cremer, Anjali and Kohl, Vanessa and Waßmer, Theresa and Stuckert, Johanna and Engemann, Victoria and Stegmaier, Kimberly and Schmitz, Katja and Schmidt, Boris (2019):
Virtual Screening Identifies Irreversible FMS-like Tyrosine Kinase 3 Inhibitors with Activity toward Resistance-Conferring Mutations.
In: Journal of Medicinal Chemistry, (5), 62. American Chemical Society, pp. 2428-2446, ISSN 0022-2623,
DOI: 10.25534/tuprints-00009651,
[Online-Edition: https://tuprints.ulb.tu-darmstadt.de/9651],
[Article]

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 and Stubba, Daniel and Cremer, Anjali and Kohl, Vanessa and Waßmer, Theresa and Stuckert, Johanna and Engemann, Victoria and Stegmaier, Kimberly and Schmitz, Katja and Schmidt, Boris
Title: Virtual Screening Identifies Irreversible FMS-like Tyrosine Kinase 3 Inhibitors with Activity toward Resistance-Conferring Mutations
Language: English
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.

Journal or Publication Title: Journal of Medicinal Chemistry
Journal volume: 62
Number: 5
Publisher: American Chemical Society
Divisions: 07 Department of Chemistry
07 Department of Chemistry > Fachgebiet Biochemie
07 Department of Chemistry > Organ Chemistry
Date Deposited: 08 Dec 2019 20:55
DOI: 10.25534/tuprints-00009651
Official URL: https://tuprints.ulb.tu-darmstadt.de/9651
URN: urn:nbn:de:tuda-tuprints-96515
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