期刊
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
卷 21, 期 23, 页码 -出版社
MDPI
DOI: 10.3390/ijms21239269
关键词
tyrosine kinases; bone marrow tyrosine kinase on chromosome X; Bruton’ s tyrosine kinase; Janus kinase 3; covalent inhibitors; chemical probes
资金
- Institutional Strategy of the University of Tubingen (German Research Foundation) [ZUK 63]
- RiSC Program of the State Ministry of Baden-Wurttemberg for Sciences, Research and Arts
- Max Buchner Research Foundation
- Postdoctoral Fellowship Program of the Baden-Wurttemberg Stiftung
- German Research Foundation (Deutsche Forschungsgemeinschaft, DFG) [EXC 2180-390900677]
- Federal Ministry of Education and Research (BMBF)
- Baden-Wurttemberg Ministry of Science as part of the Excellence Strategy of the German Federal and State Governments
- German translational cancer network DKTK
- Frankfurt Cancer Institute (FCI)
- AbbVie
- Bayer AG
- Boehringer Ingelheim
- Canada Foundation for Innovation
- Eshelman Institute for Innovation
- Genentech
- Genome Canada through Ontario Genomics Institute [OGI-196]
- EU/EFPIA/OICR/McGill/KTH/Diamond
- Innovative Medicines Initiative 2 Joint Undertaking [EUbOPEN grant] [875510]
- Janssen
- Merck KGaA (aka EMD in Canada)
- Merck Co (US)
- Pfizer
- Sao Paulo Research Foundation-FAPESP
- Takeda
- Wellcome
- University of Tubingen
- SGC
- Merck KGaA (aka EMD in US)
- Merck Co (Canada)
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.
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