ml7b00153_si_001.pdf (41.07 MB)
Identification and Characterization of JAK2 Pseudokinase Domain Small Molecule Binders
journal contribution
posted on 2017-05-17, 00:00 authored by David
E. Puleo, Kaury Kucera, Henrik M. Hammarén, Daniela Ungureanu, Ana S. Newton, Olli Silvennoinen, William L. Jorgensen, Joseph SchlessingerJanus
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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Keywords
JAK 2 pseudokinase domainpseudokinase-selective compoundscytokine-mediated JAK-STATdisplacing ATPoncogenic JAK 2 V 617F proteinoncogenic JAK mutantsprotein kinasetandem C-terminal pseudokinaseJAK 2 V 617Fmicromolar affinityJAK 2 JH 2JAK 2 Pseudokinase Domainmolecule bindershyperactivation stateTop hitspseudokinase designationRecent evidenceMolecule Binders Janus kinasestype JAK 2 proteinJAK 2 JH 2 domaintyrosine kinase
