Selective inhibitors of JAK1 targeting an isoform-restricted allosteric cysteine. Kavanagh, M. E., Horning, B. D., Khattri, R., Roy, N., Lu, J. P., Whitby, L. R., Ye, E., Brannon, J. C., Parker, A., Chick, J. M., Eissler, C. L., Wong, A. J., Rodriguez, J. L., Rodiles, S., Masuda, K., Teijaro, J. R., Simon, G. M., Patricelli, M. P., & Cravatt, B. F. Nature Chemical Biology, September, 2022. Publisher: Nature Publishing Group![Selective inhibitors of JAK1 targeting an isoform-restricted allosteric cysteine [link]](https://bibbase.org/img/filetypes/link.svg "link")
Paper doi abstract bibtex The Janus tyrosine kinase (JAK) family of non-receptor tyrosine kinases includes four isoforms (JAK1, JAK2, JAK3, and TYK2) and is responsible for signal transduction downstream of diverse cytokine receptors. JAK inhibitors have emerged as important therapies for immun(onc)ological disorders, but their use is limited by undesirable side effects presumed to arise from poor isoform selectivity, a common challenge for inhibitors targeting the ATP-binding pocket of kinases. Here we describe the chemical proteomic discovery of a druggable allosteric cysteine present in the non-catalytic pseudokinase domain of JAK1 (C817) and TYK2 (C838), but absent from JAK2 or JAK3. Electrophilic compounds selectively engaging this site block JAK1-dependent trans-phosphorylation and cytokine signaling, while appearing to act largely as ‘silent’ ligands for TYK2. Importantly, the allosteric JAK1 inhibitors do not impair JAK2-dependent cytokine signaling and are inactive in cells expressing a C817A JAK1 mutant. Our findings thus reveal an allosteric approach for inhibiting JAK1 with unprecedented isoform selectivity.
@article{kavanagh_selective_2022,
title = {Selective inhibitors of {JAK1} targeting an isoform-restricted allosteric cysteine},
copyright = {2022 The Author(s), under exclusive licence to Springer Nature America, Inc.},
issn = {1552-4469},
url = {http://www.nature.com/articles/s41589-022-01098-0},
doi = {10.1038/s41589-022-01098-0},
abstract = {The Janus tyrosine kinase (JAK) family of non-receptor tyrosine kinases includes four isoforms (JAK1, JAK2, JAK3, and TYK2) and is responsible for signal transduction downstream of diverse cytokine receptors. JAK inhibitors have emerged as important therapies for immun(onc)ological disorders, but their use is limited by undesirable side effects presumed to arise from poor isoform selectivity, a common challenge for inhibitors targeting the ATP-binding pocket of kinases. Here we describe the chemical proteomic discovery of a druggable allosteric cysteine present in the non-catalytic pseudokinase domain of JAK1 (C817) and TYK2 (C838), but absent from JAK2 or JAK3. Electrophilic compounds selectively engaging this site block JAK1-dependent trans-phosphorylation and cytokine signaling, while appearing to act largely as ‘silent’ ligands for TYK2. Importantly, the allosteric JAK1 inhibitors do not impair JAK2-dependent cytokine signaling and are inactive in cells expressing a C817A JAK1 mutant. Our findings thus reveal an allosteric approach for inhibiting JAK1 with unprecedented isoform selectivity.},
language = {en},
urldate = {2022-11-13},
journal = {Nature Chemical Biology},
author = {Kavanagh, Madeline E. and Horning, Benjamin D. and Khattri, Roli and Roy, Nilotpal and Lu, Justine P. and Whitby, Landon R. and Ye, Elva and Brannon, Jaclyn C. and Parker, Albert and Chick, Joel M. and Eissler, Christie L. and Wong, Ashley J. and Rodriguez, Joe L. and Rodiles, Socorro and Masuda, Kim and Teijaro, John R. and Simon, Gabriel M. and Patricelli, Matthew P. and Cravatt, Benjamin F.},
month = sep,
year = {2022},
note = {Publisher: Nature Publishing Group},
keywords = {Cell signalling, Immunology, Proteomics, Small molecules},
pages = {1--11},
}
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