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

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, Ami Miller, Christopher Phillips, Ralph Minter and Terence H. Rabbitts ()
Additional contact information
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

Nature Communications, 2019, vol. 10, issue 1, 1-11

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41467-019-10419-2

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