Open AccessIdentification and Characterization of JAK2 Pseudokinase Domain Small Molecule Binders
Author(s) -
D.E. Puleo,
Kaury Kucera,
Henrik Hammarén,
Daniela Ungureanu,
Ana S. Newton,
Olli Silvennoinen,
William Jorgensen,
Joseph Schlessinger
Publication year - 2017
Publication title -
acs medicinal chemistry letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.065
H-Index - 66
ISSN - 1948-5875
DOI - 10.1021/acsmedchemlett.7b00153
Subject(s) - protein kinase domain , biology , microbiology and biotechnology , kinase , mutant , janus kinase , janus kinase 2 , hek 293 cells , tyrosine kinase , signal transduction , biochemistry , receptor , gene
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.