Identification and Characterization of JAK2 Pseudokinase Domain Small Molecule Binders

Puleo, David E.; Kucera, Kaury; Hammarén, Henrik M.; Ungureanu, Daniela; Newton, Ana S.; Silvennoinen, Olli; Jorgensen, William L.; Schlessinger, Joseph

doi:10.1021/acsmedchemlett.7b00153

Identification and Characterization of JAK2 Pseudokinase Domain Small Molecule Binders

Journal Article · Mon May 22 00:00:00 EDT 2017 · ACS Medicinal Chemistry Letters

DOI:https://doi.org/10.1021/acsmedchemlett.7b00153· OSTI ID:1390880

Puleo, David E. ^[1]; Kucera, Kaury ^[1]; Hammarén, Henrik M. ^[2]; Ungureanu, Daniela ^[2]; Newton, Ana S. ^[1]; Silvennoinen, Olli ^[2]; ^[1]; ^[1]

Yale Univ., New Haven, CT (United States)
Tampere Univ. of Technology (Finland)

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.

View Accepted Manuscript (DOE)

Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (US)

Sponsoring Organization:: USDOE Office of Science (SC), Basic Energy Sciences (BES)

OSTI ID:: 1390880

Journal Information:: ACS Medicinal Chemistry Letters, Journal Name: ACS Medicinal Chemistry Letters Journal Issue: 6 Vol. 8; ISSN 1948-5875

Publisher:: American Chemical Society (ACS)Copyright Statement

Country of Publication:: United States

Language:: ENGLISH

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Prospects for pharmacological targeting of pseudokinases Kung, Jennifer E.; Jura, Natalia Nature Reviews Drug Discovery https://doi.org/10.1038/s41573-019-0018-3	journal	March 2019
Janus kinases to jakinibs: from basic insights to clinical practice Gadina, Massimo; Le, Mimi T.; Schwartz, Daniella M. Rheumatology, Vol. 58, Issue Supplement_1 https://doi.org/10.1093/rheumatology/key432	journal	February 2019
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The PEAK family of pseudokinases, their role in cell signalling and cancer Patel, Onisha; Roy, Michael J.; Murphy, James M. The FEBS Journal, Vol. 287, Issue 19 https://doi.org/10.1111/febs.15087	journal	November 2019
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