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

Nicolas Bery1, Abimael Cruz-Migoni1,2, Carole Jr Bataille3

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

Elife
|July 11, 2018
PubMed

Insights

Researchers developed novel bioluminescence resonance energy transfer (BRET)-based RAS biosensors to monitor RAS-effector interactions in living cells, aiding the discovery of new cancer drugs targeting RAS mutations.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Oncology

Background:

  • RAS proteins are frequently mutated in human cancers, presenting a significant challenge for drug development.
  • Current drug discovery for RAS mutations requires effective cell-based assays to validate in vitro findings.

Purpose of the Study:

  • To develop and validate novel RAS biosensors for monitoring RAS-effector interactions in living cells.
  • To provide a tool for assessing the efficacy of potential anti-RAS therapies.

Main Methods:

  • Development of bioluminescence resonance energy transfer (BRET)-based biosensors for KRAS, HRAS, and NRAS.
  • Incorporation of cancer-relevant RAS mutations and key RAS effectors (CRAF, PI3K, RALGDS).
  • Utilized biosensors to monitor RAS-effector interaction inhibition in cellular assays.

Main Results:

  • Demonstrated the utility of BRET-based RAS biosensors for real-time monitoring of RAS-effector interactions.
  • Showcased a RAS-binding compound as a potent inhibitor of pan-RAS-effector interactions in cells.
  • Validated the biosensors' capability to characterize anti-RAS inhibitors.

Conclusions:

  • BRET-based RAS biosensors are a robust tool for investigating RAS protein-protein interactions (PPIs) in living cells.
  • These biosensors facilitate the characterization of anti-RAS inhibitor potency and drug discovery efforts.
  • The developed biosensors can be broadly applied to study various RAS-mediated cellular processes.
Keywords:
BRETRASbiosensorscancercancer biologycell-based assaysdrug developmenthumanintracellular antibodymouseprotein-protein interaction inhibitionsmall molecule inhibitors

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