Discovery of a Novel Class of Covalent Dual Inhibitors Targeting the Protein Kinases BMX and BTK
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 kin...
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doaj-1bda5f7df0a94939ba67d4d923865a7d2020-12-05T00:04:17ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672020-12-01219269926910.3390/ijms21239269Discovery of a Novel Class of Covalent Dual Inhibitors Targeting the Protein Kinases BMX and BTKMichael Forster0Xiaojun Julia Liang1Martin Schröder2Stefan Gerstenecker3Apirat Chaikuad4Stefan Knapp5Stefan Laufer6Matthias Gehringer7Department of Pharmaceutical/Medicinal Chemistry, Institute of Pharmaceutical Sciences, Faculty of Sciences, University of Tübingen, 72076 Tübingen, GermanyDepartment of Pharmaceutical/Medicinal Chemistry, Institute of Pharmaceutical Sciences, Faculty of Sciences, University of Tübingen, 72076 Tübingen, GermanyStructural Genomics Consortium, Buchmann Institute for Molecular Life Sciences, Goethe University Frankfurt, 60438 Frankfurt am Main, GermanyDepartment of Pharmaceutical/Medicinal Chemistry, Institute of Pharmaceutical Sciences, Faculty of Sciences, University of Tübingen, 72076 Tübingen, GermanyStructural Genomics Consortium, Buchmann Institute for Molecular Life Sciences, Goethe University Frankfurt, 60438 Frankfurt am Main, GermanyStructural Genomics Consortium, Buchmann Institute for Molecular Life Sciences, Goethe University Frankfurt, 60438 Frankfurt am Main, GermanyDepartment of Pharmaceutical/Medicinal Chemistry, Institute of Pharmaceutical Sciences, Faculty of Sciences, University of Tübingen, 72076 Tübingen, GermanyDepartment of Pharmaceutical/Medicinal Chemistry, Institute of Pharmaceutical Sciences, Faculty of Sciences, University of Tübingen, 72076 Tübingen, GermanyThe 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 IC<sub>50</sub> 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.https://www.mdpi.com/1422-0067/21/23/9269tyrosine kinasesbone marrow tyrosine kinase on chromosome XBruton’s tyrosine kinaseJanus kinase 3covalent inhibitorschemical probes |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Michael Forster Xiaojun Julia Liang Martin Schröder Stefan Gerstenecker Apirat Chaikuad Stefan Knapp Stefan Laufer Matthias Gehringer |
spellingShingle |
Michael Forster Xiaojun Julia Liang Martin Schröder Stefan Gerstenecker Apirat Chaikuad Stefan Knapp Stefan Laufer Matthias Gehringer Discovery of a Novel Class of Covalent Dual Inhibitors Targeting the Protein Kinases BMX and BTK International Journal of Molecular Sciences tyrosine kinases bone marrow tyrosine kinase on chromosome X Bruton’s tyrosine kinase Janus kinase 3 covalent inhibitors chemical probes |
author_facet |
Michael Forster Xiaojun Julia Liang Martin Schröder Stefan Gerstenecker Apirat Chaikuad Stefan Knapp Stefan Laufer Matthias Gehringer |
author_sort |
Michael Forster |
title |
Discovery of a Novel Class of Covalent Dual Inhibitors Targeting the Protein Kinases BMX and BTK |
title_short |
Discovery of a Novel Class of Covalent Dual Inhibitors Targeting the Protein Kinases BMX and BTK |
title_full |
Discovery of a Novel Class of Covalent Dual Inhibitors Targeting the Protein Kinases BMX and BTK |
title_fullStr |
Discovery of a Novel Class of Covalent Dual Inhibitors Targeting the Protein Kinases BMX and BTK |
title_full_unstemmed |
Discovery of a Novel Class of Covalent Dual Inhibitors Targeting the Protein Kinases BMX and BTK |
title_sort |
discovery of a novel class of covalent dual inhibitors targeting the protein kinases bmx and btk |
publisher |
MDPI AG |
series |
International Journal of Molecular Sciences |
issn |
1661-6596 1422-0067 |
publishDate |
2020-12-01 |
description |
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 IC<sub>50</sub> 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. |
topic |
tyrosine kinases bone marrow tyrosine kinase on chromosome X Bruton’s tyrosine kinase Janus kinase 3 covalent inhibitors chemical probes |
url |
https://www.mdpi.com/1422-0067/21/23/9269 |
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