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NRAS mRNA-Degrading Bifunctional Small Molecules Induce Diverse Cellular Morphological Changes in Cancer Cells

Mao Jiang1,2,3, Daniel Hösle1,2,3, Yang Liu1,2,3

  • 1Chemical Genomics Centre, Max Planck Institute of Molecular Physiology, Dortmund, 44227, Germany.

JACS Au
|May 29, 2026
PubMed

Insights

Researchers developed novel NRAS-RIBOTACs to degrade NRAS mRNA, a new anticancer strategy. These molecules showed potential in altering cancer cell morphology, offering a new therapeutic approach.

Area of Science:

  • Oncology
  • Molecular Biology
  • Drug Discovery

Background:

  • Targeting oncogenic NRAS protein is a challenging anticancer strategy.
  • NRAS mRNA targeting offers a post-transcriptional regulatory approach with novel biological consequences.

Purpose of the Study:

  • To develop and evaluate NRAS mRNA-degrading ribonuclease targeting chimeric small molecules (NRAS-RIBOTACs).
  • To assess the phenotypic effects of NRAS-RIBOTACs using cell painting assays.

Main Methods:

  • Assembly of NRAS-RIBOTACs by conjugating a G4-NRAS binder with an RNase L binder.
  • Evaluation of NRAS-RIBOTAC efficacy on NRAS mRNA and protein expression in MD-MB-231 cells.
  • Phenotypic profiling using the cell painting assay.

Main Results:

  • NRAS-RIBOTAC 5 impacted G4-containing NRAS mRNA but not NRAS protein levels.
  • The limited impact on protein is attributed to the low abundance of G4-containing NRAS transcript.
  • Selected NRAS-RIBOTACs induced significant cellular morphological changes, demonstrating novel biological activity.

Conclusions:

  • NRAS-RIBOTACs represent a feasible strategy for targeting NRAS mRNA.
  • Phenotypic evaluation via cell painting assay revealed significant cellular effects of NRAS-RIBOTACs.
  • These findings highlight a new biological performance of RIBOTACs in cancer cells.
Keywords:
NRAS mRNARNA degradationanticancercellular morphological profileribonuclease-targeting chimera

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