دورية أكاديمية
Selective inhibitors of JAK1 targeting an isoform-restricted allosteric cysteine.
العنوان: | Selective inhibitors of JAK1 targeting an isoform-restricted allosteric cysteine. |
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المؤلفون: | Kavanagh ME; Department of Chemistry, Scripps Research, La Jolla, CA, USA., Horning BD; Vividion Therapeutics, San Diego, CA, USA., Khattri R; Vividion Therapeutics, San Diego, CA, USA., Roy N; Vividion Therapeutics, San Diego, CA, USA., Lu JP; Vividion Therapeutics, San Diego, CA, USA., Whitby LR; Vividion Therapeutics, San Diego, CA, USA., Ye E; Department of Chemistry, Scripps Research, La Jolla, CA, USA., Brannon JC; Vividion Therapeutics, San Diego, CA, USA., Parker A; Vividion Therapeutics, San Diego, CA, USA., Chick JM; Vividion Therapeutics, San Diego, CA, USA., Eissler CL; Vividion Therapeutics, San Diego, CA, USA., Wong AJ; Vividion Therapeutics, San Diego, CA, USA., Rodriguez JL; Vividion Therapeutics, San Diego, CA, USA., Rodiles S; Vividion Therapeutics, San Diego, CA, USA., Masuda K; Department of Chemistry, Scripps Research, La Jolla, CA, USA., Teijaro JR; Department of Immunology and Microbial Science, Scripps Research, La Jolla, CA, USA., Simon GM; Vividion Therapeutics, San Diego, CA, USA., Patricelli MP; Vividion Therapeutics, San Diego, CA, USA. mattp@vividion.com., Cravatt BF; Department of Chemistry, Scripps Research, La Jolla, CA, USA. cravatt@scripps.edu. |
المصدر: | Nature chemical biology [Nat Chem Biol] 2022 Dec; Vol. 18 (12), pp. 1388-1398. Date of Electronic Publication: 2022 Sep 12. |
نوع المنشور: | Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't |
اللغة: | English |
بيانات الدورية: | Publisher: Nature Pub. Group Country of Publication: United States NLM ID: 101231976 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1552-4469 (Electronic) Linking ISSN: 15524450 NLM ISO Abbreviation: Nat Chem Biol Subsets: MEDLINE |
أسماء مطبوعة: | Original Publication: New York, NY : Nature Pub. Group, [2005]- |
مواضيع طبية MeSH: | Cysteine* , Proteomics*, Signal Transduction ; Cytokines ; Protein Isoforms |
مستخلص: | 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. (© 2022. The Author(s), under exclusive licence to Springer Nature America, Inc.) |
التعليقات: | Erratum in: Nat Chem Biol. 2022 Nov;18(11):1288. doi: 10.1038/s41589-022-01181-6. (PMID: 36180594) |
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معلومات مُعتمدة: | United Kingdom WT_ Wellcome Trust; 210890 United Kingdom WT_ Wellcome Trust; R35 CA231991 United States CA NCI NIH HHS; 210890/Z/18/Z United Kingdom WT_ Wellcome Trust |
المشرفين على المادة: | K848JZ4886 (Cysteine) 0 (Cytokines) 0 (Protein Isoforms) |
تواريخ الأحداث: | Date Created: 20220913 Date Completed: 20221125 Latest Revision: 20240611 |
رمز التحديث: | 20240611 |
مُعرف محوري في PubMed: | PMC7614775 |
DOI: | 10.1038/s41589-022-01098-0 |
PMID: | 36097295 |
قاعدة البيانات: | MEDLINE |
تدمد: | 1552-4469 |
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DOI: | 10.1038/s41589-022-01098-0 |