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

Autor:	Bery N; MRC Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, United Kingdom., Cruz-Migoni A; MRC Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, United Kingdom.; Research Complex at Harwell, Rutherford Appleton Laboratory, Didcot, United Kingdom., Bataille CJ; Chemistry Research Laboratory, Oxford, United Kingdom., Quevedo CE; MRC Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, United Kingdom., Tulmin H; MRC Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, United Kingdom., Miller A; MRC Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, United Kingdom., Russell A; Chemistry Research Laboratory, Oxford, United Kingdom., Phillips SE; Department of Biochemistry, University of Oxford, Oxford, United Kingdom., Carr SB; Research Complex at Harwell, Rutherford Appleton Laboratory, Didcot, United Kingdom.; Department of Biochemistry, University of Oxford, Oxford, United Kingdom., Rabbitts TH; MRC Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, United Kingdom.
Jazyk:	angličtina
Zdroj:	ELife [Elife] 2018 Jul 10; Vol. 7. Date of Electronic Publication: 2018 Jul 10.
DOI:	10.7554/eLife.37122
Abstrakt:	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. Competing Interests: NB, CB, CQ, HT, AM, SP, SC, TR No competing interests declared, AC Employed by Immunocore; no other competing financial interests to declare, AR Founder of OxStem; no other competing financial interests to declare (© 2018, Bery et al.)
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu