ml7b00153_si_001.pdf (41.07 MB)
Identification and Characterization of JAK2 Pseudokinase Domain Small Molecule Binders
journal contributionposted 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 Schlessinger
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.
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