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A resource for exploring the understudied human kinome for research and therapeutic opportunities

View ORCID ProfileNienke Moret, View ORCID ProfileChangchang Liu, View ORCID ProfileBenjamin M. Gyori, View ORCID ProfileJohn A. Bachman, View ORCID ProfileAlbert Steppi, View ORCID ProfileClemens Hug, View ORCID ProfileRahil Taujale, View ORCID ProfileLiang-Chin Huang, View ORCID ProfileMatthew E. Berginski, View ORCID ProfileShawn M. Gomez, View ORCID ProfileNatarajan Kannan, View ORCID ProfilePeter K. Sorger
doi: https://doi.org/10.1101/2020.04.02.022277
Nienke Moret
1The NIH Understudied Kinome Consortium
2Laboratory of Systems Pharmacology, Department of Systems Biology, Harvard Program in Therapeutic Science, Harvard Medical School, Boston, Massachusetts 02115, USA
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  • ORCID record for Nienke Moret
Changchang Liu
1The NIH Understudied Kinome Consortium
2Laboratory of Systems Pharmacology, Department of Systems Biology, Harvard Program in Therapeutic Science, Harvard Medical School, Boston, Massachusetts 02115, USA
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Benjamin M. Gyori
2Laboratory of Systems Pharmacology, Department of Systems Biology, Harvard Program in Therapeutic Science, Harvard Medical School, Boston, Massachusetts 02115, USA
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John A. Bachman
2Laboratory of Systems Pharmacology, Department of Systems Biology, Harvard Program in Therapeutic Science, Harvard Medical School, Boston, Massachusetts 02115, USA
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Albert Steppi
2Laboratory of Systems Pharmacology, Department of Systems Biology, Harvard Program in Therapeutic Science, Harvard Medical School, Boston, Massachusetts 02115, USA
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Clemens Hug
2Laboratory of Systems Pharmacology, Department of Systems Biology, Harvard Program in Therapeutic Science, Harvard Medical School, Boston, Massachusetts 02115, USA
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Rahil Taujale
3Institute of Bioinformatics, University of Georgia, Athens, GA, 30602 USA
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Liang-Chin Huang
3Institute of Bioinformatics, University of Georgia, Athens, GA, 30602 USA
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  • ORCID record for Liang-Chin Huang
Matthew E. Berginski
1The NIH Understudied Kinome Consortium
4Department of Pharmacology, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
5Joint Department of Biomedical Engineering at the University of North Carolina at Chapel Hill and North Carolina State University, Chapel Hill, NC 27599, USA
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Shawn M. Gomez
1The NIH Understudied Kinome Consortium
4Department of Pharmacology, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
5Joint Department of Biomedical Engineering at the University of North Carolina at Chapel Hill and North Carolina State University, Chapel Hill, NC 27599, USA
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Natarajan Kannan
1The NIH Understudied Kinome Consortium
3Institute of Bioinformatics, University of Georgia, Athens, GA, 30602 USA
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Peter K. Sorger
1The NIH Understudied Kinome Consortium
2Laboratory of Systems Pharmacology, Department of Systems Biology, Harvard Program in Therapeutic Science, Harvard Medical School, Boston, Massachusetts 02115, USA
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  • For correspondence: peter_sorger@hms.harvard.edu sorger_admin@hms.harvard.edu
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ABSTRACT

The functions of protein kinases have been widely studied and over 60 kinase inhibitors are FDA-approved drugs. Membership in the human kinome is nonetheless subject to multiple overlapping and inconsistent definitions and is unevenly studied, complicating functional genomics and chemical genetics. We describe objective criteria for refining the definition of the human kinome to comprise an extended set of 710 kinase domains and a more narrowly curated set of 557 protein kinase like (PKL) domains. An online tool (www.kinome.org) makes it possible to sort these sets on multiple structural and functional criteria. Focusing on the least studied one-third of the kinome we find that many proteins are differentially expressed, essential in multiple cell lines, and mutated in the Cancer Genome Atlas. We show that some understudied kinases are high affinity off-targets of clinical-grade compounds and approved drugs and we describe an optimized small molecule library making use of this information for selective kinome perturbation. We conclude that the understudied kinome contains physiologically important proteins, including possible targets for future drug discovery campaigns.

Competing Interest Statement

The authors have declared no competing interest.

Footnotes

  • https://www.synapse.org/#!Synapse:syn21892220/wiki/601923

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY 4.0 International license.
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Posted March 11, 2021.
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A resource for exploring the understudied human kinome for research and therapeutic opportunities
Nienke Moret, Changchang Liu, Benjamin M. Gyori, John A. Bachman, Albert Steppi, Clemens Hug, Rahil Taujale, Liang-Chin Huang, Matthew E. Berginski, Shawn M. Gomez, Natarajan Kannan, Peter K. Sorger
bioRxiv 2020.04.02.022277; doi: https://doi.org/10.1101/2020.04.02.022277
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A resource for exploring the understudied human kinome for research and therapeutic opportunities
Nienke Moret, Changchang Liu, Benjamin M. Gyori, John A. Bachman, Albert Steppi, Clemens Hug, Rahil Taujale, Liang-Chin Huang, Matthew E. Berginski, Shawn M. Gomez, Natarajan Kannan, Peter K. Sorger
bioRxiv 2020.04.02.022277; doi: https://doi.org/10.1101/2020.04.02.022277

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