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Chemical genetics strategy to profile kinase target engagement reveals role of FES in neutrophil phagocytosis

Author

Listed:
  • Tom van der Wel

    (Leiden Institute of Chemistry, Leiden University & Oncode Institute)

  • Riet Hilhorst

    (PamGene International BV)

  • Hans den Dulk

    (Leiden Institute of Chemistry, Leiden University & Oncode Institute)

  • Tim van den Hooven

    (PamGene International BV)

  • Nienke M. Prins

    (Leiden Institute of Chemistry, Leiden University & Oncode Institute)

  • Joost A. P. M. Wijnakker

    (Leiden Institute of Chemistry, Leiden University & Oncode Institute)

  • Bogdan I. Florea

    (Leiden Institute of Chemistry, Leiden University)

  • Eelke B. Lenselink

    (Leiden Academic Centre for Drug Research, Leiden University)

  • Gerard J. P. van Westen

    (Leiden Academic Centre for Drug Research, Leiden University)

  • Rob Ruijtenbeek

    (PamGene International BV)

  • Herman S. Overkleeft

    (Leiden Institute of Chemistry, Leiden University)

  • Allard Kaptein

    (Covalution Biosciences BV)

  • Tjeerd Barf

    (Covalution Biosciences BV)

  • Mario van der Stelt

    (Leiden Institute of Chemistry, Leiden University & Oncode Institute)

Abstract

Chemical tools to monitor drug-target engagement of endogenously expressed protein kinases are highly desirable for preclinical target validation in drug discovery. Here, we describe a chemical genetics strategy to selectively study target engagement of endogenous kinases. By substituting a serine residue into cysteine at the DFG-1 position in the ATP-binding pocket, we sensitize the non-receptor tyrosine kinase FES towards covalent labeling by a complementary fluorescent chemical probe. This mutation is introduced in the endogenous FES gene of HL-60 cells using CRISPR/Cas9 gene editing. Leveraging the temporal and acute control offered by our strategy, we show that FES activity is dispensable for differentiation of HL-60 cells towards macrophages. Instead, FES plays a key role in neutrophil phagocytosis via SYK kinase activation. This chemical genetics strategy holds promise as a target validation method for kinases.

Suggested Citation

  • Tom van der Wel & Riet Hilhorst & Hans den Dulk & Tim van den Hooven & Nienke M. Prins & Joost A. P. M. Wijnakker & Bogdan I. Florea & Eelke B. Lenselink & Gerard J. P. van Westen & Rob Ruijtenbeek & , 2020. "Chemical genetics strategy to profile kinase target engagement reveals role of FES in neutrophil phagocytosis," Nature Communications, Nature, vol. 11(1), pages 1-20, December.
    • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-17027-5
    DOI: 10.1038/s41467-020-17027-5
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