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

Title: Identification and Characterization of JAK2 Pseudokinase Domain Small Molecule Binders

Abstract

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.

Authors:

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)

Publication Date:: Mon May 22 00:00:00 EDT 2017

Research Org.:: Argonne National Laboratory (ANL), Argonne, IL (United States)

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

OSTI Identifier:: 1390880

Grant/Contract Number:: 1S10OD018007

Resource Type:: Accepted Manuscript

Journal Name:: ACS Medicinal Chemistry Letters

Additional Journal Information:: Journal Volume: 8; Journal Issue: 6; Journal ID: ISSN 1948-5875

Publisher:: American Chemical Society (ACS)

Country of Publication:: United States

Language:: ENGLISH

Subject:: 59 BASIC BIOLOGICAL SCIENCES; JAK2; Pseudokinase; JH2; MPN; Small molecule

Citation Formats


                    Puleo, David E., Kucera, Kaury, Hammarén, Henrik M., Ungureanu, Daniela, Newton, Ana S., Silvennoinen, Olli, Jorgensen, William L., and Schlessinger, Joseph. Identification and Characterization of JAK2 Pseudokinase Domain Small Molecule Binders.  United States: N. p., 2017. 
Web.  doi:10.1021/acsmedchemlett.7b00153.

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                    Puleo, David E., Kucera, Kaury, Hammarén, Henrik M., Ungureanu, Daniela, Newton, Ana S., Silvennoinen, Olli, Jorgensen, William L., & Schlessinger, Joseph. Identification and Characterization of JAK2 Pseudokinase Domain Small Molecule Binders.  United States.  https://doi.org/10.1021/acsmedchemlett.7b00153

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                    Puleo, David E., Kucera, Kaury, Hammarén, Henrik M., Ungureanu, Daniela, Newton, Ana S., Silvennoinen, Olli, Jorgensen, William L., and Schlessinger, Joseph. Mon .  
"Identification and Characterization of JAK2 Pseudokinase Domain Small Molecule Binders".  United States.  https://doi.org/10.1021/acsmedchemlett.7b00153.  https://www.osti.gov/servlets/purl/1390880.

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@article{osti_1390880,

  title        = {Identification and Characterization of JAK2 Pseudokinase Domain Small Molecule Binders},

  author       = {Puleo, David E. and Kucera, Kaury and Hammarén, Henrik M. and Ungureanu, Daniela and Newton, Ana S. and Silvennoinen, Olli and Jorgensen, William L. and Schlessinger, Joseph},

  abstractNote = {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.},

  doi          = {10.1021/acsmedchemlett.7b00153},

  journal      = {ACS Medicinal Chemistry Letters},

  number       = 6,

  volume       = 8,

  place        = {United States},

  year         = {Mon May 22 00:00:00 EDT 2017},

  month        = {Mon May 22 00:00:00 EDT 2017}

}

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https://doi.org/10.1021/acsmedchemlett.7b00153

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Cited by: 28 works

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Figures / Tables:

Figure 1: Chemical structures of the two top hits from the fluorescence polarization screen, (A) JNJ-7706621 and (B) AT9283.

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Works referenced in this record:

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Hammarén, Henrik M.; Ungureanu, Daniela; Grisouard, Jean
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Structure of the pseudokinase-kinase domains from protein kinase TYK2 reveals a mechanism for Janus kinase (JAK) autoinhibition
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Lupardus, P. J.; Ultsch, M.; Wallweber, H.
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Autoinhibition of Jak2 Tyrosine Kinase Is Dependent on Specific Regions in Its Pseudokinase Domain
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Saharinen, Pipsa; Vihinen, Mauno; Silvennoinen, Olli
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Works referencing / citing this record:

Covalent inhibitors of EGFR family protein kinases induce degradation of human Tribbles 2 (TRIB2) pseudokinase in cancer cells
journal, September 2018

Foulkes, Daniel M.; Byrne, Dominic P.; Yeung, Wayland
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Kung, Jennifer E.; Jura, Natalia
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Gadina, Massimo; Le, Mimi T.; Schwartz, Daniella M.
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Patel, Onisha; Roy, Michael J.; Murphy, James M.
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JAK inhibitors for the treatment of myeloproliferative neoplasms and other disorders
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Similar Records

Title: Identification and Characterization of JAK2 Pseudokinase Domain Small Molecule Binders

Abstract

Citation Formats

Figures / Tables:

The JAK-STAT Pathway: Impact on Human Disease and Therapeutic Intervention journal, January 2015

Regulation of the Jak2 Tyrosine Kinase by Its Pseudokinase Domain journal, May 2000

Structure of the pseudokinase-kinase domains from protein kinase TYK2 reveals a mechanism for Janus kinase (JAK) autoinhibition journal, May 2014

Molecular basis for pseudokinase-dependent autoinhibition of JAK2 tyrosine kinase journal, June 2014

Acquired mutation of the tyrosine kinase JAK2 in human myeloproliferative disorders journal, March 2005

A unique clonal JAK2 mutation leading to constitutive signalling causes polycythaemia vera journal, March 2005

A Gain-of-Function Mutation of JAK2 in Myeloproliferative Disorders journal, April 2005

Activating mutation in the tyrosine kinase JAK2 in polycythemia vera, essential thrombocythemia, and myeloid metaplasia with myelofibrosis journal, April 2005

Structure of a pseudokinase-domain switch that controls oncogenic activation of Jak kinases journal, September 2013

The pseudokinase domain of JAK2 is a dual-specificity protein kinase that negatively regulates cytokine signaling journal, August 2011

Crystal structures of the JAK2 pseudokinase domain and the pathogenic mutant V617F journal, July 2012

Structural and Functional Characterization of the JH2 Pseudokinase Domain of JAK Family Tyrosine Kinase 2 (TYK2) journal, November 2015

ATP binding to the pseudokinase domain of JAK2 is critical for pathogenic activation journal, March 2015

1-Acyl-1 H -[1,2,4]triazole-3,5-diamine Analogues as Novel and Potent Anticancer Cyclin-Dependent Kinase Inhibitors: Synthesis and Evaluation of Biological Activities journal, June 2005

A quantitative analysis of kinase inhibitor selectivity journal, January 2008

Fragment-Based Discovery of the Pyrazol-4-yl Urea (AT9283), a Multitargeted Kinase Inhibitor with Potent Aurora Kinase Activity † journal, January 2009

JAK2 V617F Constitutive Activation Requires JH2 Residue F595: A Pseudokinase Domain Target for Specific Inhibitors journal, June 2010

Structure of the pseudokinase-kinase domains from protein kinase TYK2 reveals a mechanism for Janus kinase (JAK) autoinhibition journal, May 2014

Autoinhibition of Jak2 Tyrosine Kinase Is Dependent on Specific Regions in Its Pseudokinase Domain journal, April 2003

Regulation of the Jak2 Tyrosine Kinase by Its Pseudokinase Domain journal, January 2000

Covalent inhibitors of EGFR family protein kinases induce degradation of human Tribbles 2 (TRIB2) pseudokinase in cancer cells journal, September 2018

Prospects for pharmacological targeting of pseudokinases journal, March 2019

Janus kinases to jakinibs: from basic insights to clinical practice journal, February 2019

The PEAK family of pseudokinases, their role in cell signalling and cancer journal, November 2019

JAK inhibitors for the treatment of myeloproliferative neoplasms and other disorders journal, January 2018

Repurposing covalent EGFR/HER2 inhibitors for on-target degradation of human Tribbles 2 (TRIB2) pseudokinase posted_content, April 2018

JAK inhibitors for the treatment of myeloproliferative neoplasms and other disorders journal, January 2018

The JAK-STAT Pathway: Impact on Human Disease and Therapeutic Intervention
journal, January 2015

Regulation of the Jak2 Tyrosine Kinase by Its Pseudokinase Domain
journal, May 2000

Structure of the pseudokinase-kinase domains from protein kinase TYK2 reveals a mechanism for Janus kinase (JAK) autoinhibition
journal, May 2014

Molecular basis for pseudokinase-dependent autoinhibition of JAK2 tyrosine kinase
journal, June 2014

Acquired mutation of the tyrosine kinase JAK2 in human myeloproliferative disorders
journal, March 2005

A unique clonal JAK2 mutation leading to constitutive signalling causes polycythaemia vera
journal, March 2005

A Gain-of-Function Mutation of JAK2 in Myeloproliferative Disorders
journal, April 2005

Activating mutation in the tyrosine kinase JAK2 in polycythemia vera, essential thrombocythemia, and myeloid metaplasia with myelofibrosis
journal, April 2005

Structure of a pseudokinase-domain switch that controls oncogenic activation of Jak kinases
journal, September 2013

The pseudokinase domain of JAK2 is a dual-specificity protein kinase that negatively regulates cytokine signaling
journal, August 2011

Crystal structures of the JAK2 pseudokinase domain and the pathogenic mutant V617F
journal, July 2012

Structural and Functional Characterization of the JH2 Pseudokinase Domain of JAK Family Tyrosine Kinase 2 (TYK2)
journal, November 2015

ATP binding to the pseudokinase domain of JAK2 is critical for pathogenic activation
journal, March 2015

1-Acyl-1 H -[1,2,4]triazole-3,5-diamine Analogues as Novel and Potent Anticancer Cyclin-Dependent Kinase Inhibitors: Synthesis and Evaluation of Biological Activities
journal, June 2005

A quantitative analysis of kinase inhibitor selectivity
journal, January 2008

Fragment-Based Discovery of the Pyrazol-4-yl Urea (AT9283), a Multitargeted Kinase Inhibitor with Potent Aurora Kinase Activity ^†
journal, January 2009

JAK2 V617F Constitutive Activation Requires JH2 Residue F595: A Pseudokinase Domain Target for Specific Inhibitors
journal, June 2010

Structure of the pseudokinase-kinase domains from protein kinase TYK2 reveals a mechanism for Janus kinase (JAK) autoinhibition
journal, May 2014

Autoinhibition of Jak2 Tyrosine Kinase Is Dependent on Specific Regions in Its Pseudokinase Domain
journal, April 2003

Regulation of the Jak2 Tyrosine Kinase by Its Pseudokinase Domain
journal, January 2000

Covalent inhibitors of EGFR family protein kinases induce degradation of human Tribbles 2 (TRIB2) pseudokinase in cancer cells
journal, September 2018

Prospects for pharmacological targeting of pseudokinases
journal, March 2019

Janus kinases to jakinibs: from basic insights to clinical practice
journal, February 2019

The PEAK family of pseudokinases, their role in cell signalling and cancer
journal, November 2019

JAK inhibitors for the treatment of myeloproliferative neoplasms and other disorders
journal, January 2018

Repurposing covalent EGFR/HER2 inhibitors for on-target degradation of human Tribbles 2 (TRIB2) pseudokinase
posted_content, April 2018

JAK inhibitors for the treatment of myeloproliferative neoplasms and other disorders
journal, January 2018