BRET-based RAS biosensors that show a novel small molecule is an inhibitor of RAS-effector protein-protein interactions

Author:

Bery Nicolas1ORCID,Cruz-Migoni Abimael12,Bataille Carole JR3,Quevedo Camilo E1,Tulmin Hanna1,Miller Ami1,Russell Angela3,Phillips Simon EV4,Carr Stephen B24,Rabbitts Terence H1ORCID

Affiliation:

1. MRC Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, United Kingdom

2. Research Complex at Harwell, Rutherford Appleton Laboratory, Didcot, United Kingdom

3. Chemistry Research Laboratory, Oxford, United Kingdom

4. Department of Biochemistry, University of Oxford, Oxford, United Kingdom

Abstract

The RAS family of proteins is amongst the most highly mutated in human cancers and has so far eluded drug therapy. Currently, much effort is being made to discover mutant RAS inhibitors and in vitro screening for RAS-binding drugs must be followed by cell-based assays. Here, we have developed a robust set of bioluminescence resonance energy transfer (BRET)-based RAS biosensors that enable monitoring of RAS-effector interaction inhibition in living cells. These include KRAS, HRAS and NRAS and a variety of different mutations that mirror those found in human cancers with the major RAS effectors such as CRAF, PI3K and RALGDS. We highlighted the utility of these RAS biosensors by showing a RAS-binding compound is a potent pan-RAS-effector interactions inhibitor in cells. The RAS biosensors represent a useful tool to investigate and characterize the potency of anti-RAS inhibitors in cells and more generally any RAS protein-protein interaction (PPI) in cells.

Funder

Medical Research Council

Wellcome

Bloodwise

Publisher

eLife Sciences Publications, Ltd

Subject

General Immunology and Microbiology,General Biochemistry, Genetics and Molecular Biology,General Medicine,General Neuroscience

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