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KRAS-specific inhibition using a DARPin binding to a site in the allosteric lobe

Author

Listed:
  • Nicolas Bery

    (MRC Molecular Haematology Unit, University of Oxford, John Radcliffe Hospital)

  • Sandrine Legg

    (Milstein Building Granta Park)

  • Judit Debreczeni

    (AstraZeneca, Darwin Building, Cambridge Science Park, Milton Road)

  • Jason Breed

    (AstraZeneca, Darwin Building, Cambridge Science Park, Milton Road)

  • Kevin Embrey

    (AstraZeneca, Darwin Building, Cambridge Science Park, Milton Road)

  • Christopher Stubbs

    (AstraZeneca, Darwin Building, Cambridge Science Park, Milton Road)

  • Paulina Kolasinska-Zwierz

    (Milstein Building Granta Park)

  • Nathalie Barrett

    (Milstein Building Granta Park)

  • Rose Marwood

    (Milstein Building Granta Park)

  • Jo Watson

    (Milstein Building Granta Park)

  • Jon Tart

    (AstraZeneca, Darwin Building, Cambridge Science Park, Milton Road)

  • Ross Overman

    (AstraZeneca, Darwin Building, Cambridge Science Park, Milton Road)

  • Ami Miller

    (MRC Molecular Haematology Unit, University of Oxford, John Radcliffe Hospital)

  • Christopher Phillips

    (AstraZeneca, Darwin Building, Cambridge Science Park, Milton Road)

  • Ralph Minter

    (Milstein Building Granta Park)

  • Terence H. Rabbitts

    (MRC Molecular Haematology Unit, University of Oxford, John Radcliffe Hospital)

Abstract

Inhibiting the RAS oncogenic protein has largely been through targeting the switch regions that interact with signalling effector proteins. Here, we report designed ankyrin repeat proteins (DARPins) macromolecules that specifically inhibit the KRAS isoform by binding to an allosteric site encompassing the region around KRAS-specific residue histidine 95 at the helix α3/loop 7/helix α4 interface. We show that these DARPins specifically inhibit KRAS/effector interactions and the dependent downstream signalling pathways in cancer cells. Binding by the DARPins at that region influences KRAS/effector interactions in different ways, including KRAS nucleotide exchange and inhibiting KRAS dimerization at the plasma membrane. These results highlight the importance of targeting the α3/loop 7/α4 interface, a previously untargeted site in RAS, for specifically inhibiting KRAS function.

Suggested Citation

  • Nicolas Bery & Sandrine Legg & Judit Debreczeni & Jason Breed & Kevin Embrey & Christopher Stubbs & Paulina Kolasinska-Zwierz & Nathalie Barrett & Rose Marwood & Jo Watson & Jon Tart & Ross Overman & , 2019. "KRAS-specific inhibition using a DARPin binding to a site in the allosteric lobe," Nature Communications, Nature, vol. 10(1), pages 1-11, December.
    • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-10419-2
    DOI: 10.1038/s41467-019-10419-2
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