Identification and Characterization of JAK2 Pseudokinase Domain Small Molecule Binders

被引：34

作者：

Puleo, David E. ^{[1
]}

Kucera, Kaury ^{[1
]}

Hammaren, Henrik M. ^{[3
]}

Ungureanu, Daniela ^{[3
]}

Newton, Ana S. ^{[2
]}

Silvennoinen, Olli ^{[3
]}

Jorgensen, William L. ^{[2
]}

Schlessinger, Joseph ^{[1
]}

机构：

[1] Yale Univ, Dept Pharmacol, New Haven, CT 06520 USA

[2] Yale Univ, Dept Chem, 225 Prospect St, New Haven, CT 06520 USA

[3] Univ Tampere, Fac Med & Biosci, Tampere 33014, Finland

来源：

ACS MEDICINAL CHEMISTRY LETTERS | 2017年 / 8卷 / 06期

关键词：

JAK2; Pseudokinase; JH2; MPN; Small molecule; TYROSINE KINASE JAK2; MYELOPROLIFERATIVE DISORDERS; POLYCYTHEMIA-VERA; PROTEIN-KINASE; MUTATION; AUTOINHIBITION; ACTIVATION; INHIBITOR; DISEASE; TYK2;

D O I：

10.1021/acsmedchemlett.7b00153

中图分类号：

R914 [药物化学];

学科分类号：

100705 [微生物与生化药学];

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.

引用

页码：618 / 621

页数：4

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