蛋白激酶结构域
生物
细胞生物学
激酶
突变体
贾纳斯激酶
Janus激酶2
HEK 293细胞
酪氨酸激酶
信号转导
生物化学
受体
基因
作者
D.E. Puleo,Kaury Kucera,Henrik Hammarén,Daniela Ungureanu,Ana S. Newton,Olli Silvennoinen,William Jorgensen,Joseph Schlessinger
标识
DOI:10.1021/acsmedchemlett.7b00153
摘要
Janus kinases (JAKs) regulate hematopoiesis via the cytokine-mediated JAK-STAT signaling pathway. JAKs contain tandem C-terminal pseudokinase (JH2) and tyrosine kinase (JH1) domains. The JAK2 pseudokinase domain adopts a protein kinase fold and, despite its pseudokinase designation, binds ATP with micromolar affinity. Recent evidence shows that displacing ATP from the JAK2 JH2 domain alters the hyperactivation state of the oncogenic JAK2 V617F protein while sparing the wild type JAK2 protein. In this study, small molecule binders of JAK2 JH2 were identified via an in vitro screen. Top hits were characterized using biophysical and structural approaches. Development of pseudokinase-selective compounds may offer novel pharmacological opportunities for treating cancers driven by JAK2 V617F and other oncogenic JAK mutants.
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