变构调节
酪氨酸激酶2
贾纳斯激酶
磷酸化
信号转导
受体酪氨酸激酶
化学
生物化学
激酶
细胞因子受体
细胞生物学
Janus激酶1
酪氨酸激酶
生物
受体
血小板源性生长因子受体
生长因子
作者
Madeline E. Kavanagh,Benjamin D. Horning,Roli Khattri,Nilotpal Roy,Justine P Lu,Landon R. Whitby,Elva Ye,Jaclyn C Brannon,Albert E. Parker,Joel M. Chick,Christie L. Eissler,Ashley P Wong,Joe L Rodriguez,Socorro Rodiles,Kim Masuda,John R. Teijaro,Gabriel Simón,Matthew P. Patricelli,Benjamin F. Cravatt
标识
DOI:10.1038/s41589-022-01098-0
摘要
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.
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