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Article

Discovery of a Novel Class of Covalent Dual Inhibitors Targeting the Protein Kinases BMX and BTK

1
Department of Pharmaceutical/Medicinal Chemistry, Institute of Pharmaceutical Sciences, Faculty of Sciences, University of Tübingen, 72076 Tübingen, Germany
2
Cluster of Excellence iFIT (EXC 2180) ‘Image-Guided & Functionally Instructed Tumor Therapies’, University of Tübingen, 72076 Tübingen, Germany
3
Structural Genomics Consortium, Goethe University Frankfurt, Buchmann Institute for Molecular Life Sciences, Max-von-Laue-Straße 15, 60438 Frankfurt am Main, Germany
4
Institute of Pharmaceutical Chemistry, Goethe University Frankfurt, Buchmann Institute for Molecular Life Sciences, Max-von-Laue-Straße 9, 60438 Frankfurt am Main, Germany
5
Frankfurt Cancer Institute (FCI) and German Translational Cancer Network (DKTK) Site Frankfurt/Mainz, 60438 Frankfurt am Main, Germany
6
Tübingen Center for Academic Drug Discovery (TüCAD2), 72076 Tübingen, Germany
*
Author to whom correspondence should be addressed.
These authors contributed equally to this work.
Int. J. Mol. Sci. 2020, 21(23), 9269; https://doi.org/10.3390/ijms21239269
Received: 22 October 2020 / Revised: 29 November 2020 / Accepted: 1 December 2020 / Published: 4 December 2020
The nonreceptor tyrosine TEC kinases are key regulators of the immune system and play a crucial role in the pathogenesis of diverse hematological malignancies. In contrast to the substantial efforts in inhibitor development for Bruton’s tyrosine kinase (BTK), specific inhibitors of the other TEC kinases, including the bone marrow tyrosine kinase on chromosome X (BMX), remain sparse. Here we present a novel class of dual BMX/BTK inhibitors, which were designed from irreversible inhibitors of Janus kinase (JAK) 3 targeting a cysteine located within the solvent-exposed front region of the ATP binding pocket. Structure-guided design exploiting the differences in the gatekeeper residues enabled the achievement of high selectivity over JAK3 and certain other kinases harboring a sterically demanding residue at this position. The most active compounds inhibited BMX and BTK with apparent IC50 values in the single digit nanomolar range or below showing moderate selectivity within the TEC family and potent cellular target engagement. These compounds represent an important first step towards selective chemical probes for the protein kinase BMX. View Full-Text
Keywords: tyrosine kinases; bone marrow tyrosine kinase on chromosome X; Bruton’s tyrosine kinase; Janus kinase 3; covalent inhibitors; chemical probes tyrosine kinases; bone marrow tyrosine kinase on chromosome X; Bruton’s tyrosine kinase; Janus kinase 3; covalent inhibitors; chemical probes
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MDPI and ACS Style

Forster, M.; Liang, X.J.; Schröder, M.; Gerstenecker, S.; Chaikuad, A.; Knapp, S.; Laufer, S.; Gehringer, M. Discovery of a Novel Class of Covalent Dual Inhibitors Targeting the Protein Kinases BMX and BTK. Int. J. Mol. Sci. 2020, 21, 9269. https://doi.org/10.3390/ijms21239269

AMA Style

Forster M, Liang XJ, Schröder M, Gerstenecker S, Chaikuad A, Knapp S, Laufer S, Gehringer M. Discovery of a Novel Class of Covalent Dual Inhibitors Targeting the Protein Kinases BMX and BTK. International Journal of Molecular Sciences. 2020; 21(23):9269. https://doi.org/10.3390/ijms21239269

Chicago/Turabian Style

Forster, Michael, Xiaojun J. Liang, Martin Schröder, Stefan Gerstenecker, Apirat Chaikuad, Stefan Knapp, Stefan Laufer, and Matthias Gehringer. 2020. "Discovery of a Novel Class of Covalent Dual Inhibitors Targeting the Protein Kinases BMX and BTK" International Journal of Molecular Sciences 21, no. 23: 9269. https://doi.org/10.3390/ijms21239269

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