Structural and functional characterization of a DARPin which inhibits Ras nucleotide exchange

Sandrine Guillard, Paulina Kolasinska-Zwierz, Judit Debreczeni, Jason Breed, Jing Zhang, Nicolas Bery, Rose Marwood, Jon Tart, Ross Overman, Pawel Stocki, Bina Mistry, Christopher Phillips, Terence Rabbitts, Ronald Jackson and Ralph Minter ()
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Sandrine Guillard: Antibody Discovery and Protein Engineering, MedImmune
Paulina Kolasinska-Zwierz: Antibody Discovery and Protein Engineering, MedImmune
Judit Debreczeni: Discovery Sciences, Innovative Medicines and Early Development, AstraZeneca
Jason Breed: Discovery Sciences, Innovative Medicines and Early Development, AstraZeneca
Jing Zhang: MRC Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford
Nicolas Bery: MRC Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford
Rose Marwood: Antibody Discovery and Protein Engineering, MedImmune
Jon Tart: Discovery Sciences, Innovative Medicines and Early Development, AstraZeneca
Ross Overman: Discovery Sciences, Innovative Medicines and Early Development, AstraZeneca
Pawel Stocki: Antibody Discovery and Protein Engineering, MedImmune
Bina Mistry: Antibody Discovery and Protein Engineering, MedImmune
Christopher Phillips: Discovery Sciences, Innovative Medicines and Early Development, AstraZeneca
Terence Rabbitts: MRC Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford
Ronald Jackson: Antibody Discovery and Protein Engineering, MedImmune
Ralph Minter: Antibody Discovery and Protein Engineering, MedImmune

Nature Communications, 2017, vol. 8, issue 1, 1-11

Abstract: Abstract Ras mutations are the oncogenic drivers of many human cancers and yet there are still no approved Ras-targeted cancer therapies. Inhibition of Ras nucleotide exchange is a promising new approach but better understanding of this mechanism of action is needed. Here we describe an antibody mimetic, DARPin K27, which inhibits nucleotide exchange of Ras. K27 binds preferentially to the inactive Ras GDP form with a Kd of 4 nM and structural studies support its selectivity for inactive Ras. Intracellular expression of K27 significantly reduces the amount of active Ras, inhibits downstream signalling, in particular the levels of phosphorylated ERK, and slows the growth in soft agar of HCT116 cells. K27 is a potent, non-covalent inhibitor of nucleotide exchange, showing consistent effects across different isoforms of Ras, including wild-type and oncogenic mutant forms.

Date: 2017
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DOI: 10.1038/ncomms16111

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