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Oligomycins as inhibitors of K-Ras plasma membrane localisation

A A Salim1, L Tan, X-C Huang

  • 1Institute for Molecular Bioscience, The University of Queensland, St Lucia, QLD 4072, Australia. r.capon@uq.edu.au.

Organic & Biomolecular Chemistry
|November 14, 2015
PubMed

Insights

Researchers discovered novel oligomycins that effectively block oncogenic K-Ras protein at the plasma membrane. These compounds show potential as cancer chemotherapeutics by inhibiting K-Ras localization and exhibiting cytotoxicity against colorectal cancer cells.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Pharmacology

Background:

  • Oncogenic mutant K-Ras requires plasma membrane localization for function in various cancers.
  • Inhibiting K-Ras plasma membrane localization presents a therapeutic strategy for cancer treatment.

Purpose of the Study:

  • To identify novel inhibitors of K-Ras plasma membrane localization from microbial sources.
  • To characterize the structures and anti-cancer properties of identified compounds.

Main Methods:

  • Screening of a microbial extract library using a high-content cell-based assay.
  • Cultivation, fractionation, and spectroscopic analysis of Streptomyces strains to isolate and identify compounds.
  • Cell viability assays and assessment of P-glycoprotein inhibition.

Main Results:

  • Oligomycins A-E, 21-hydroxy-oligomycin A, 21-hydroxy-oligomycin C, and 40-hydroxy-oligomycin B were isolated and characterized.
  • All tested oligomycins (1-8) demonstrated potent inhibition of K-Ras plasma membrane localization (IC50 ~ 1.5-14 nM).
  • Compounds exhibited cytotoxicity against colorectal carcinoma cells and inhibited P-glycoprotein.

Conclusions:

  • Oligomycin compounds are potent inhibitors of oncogenic K-Ras plasma membrane localization.
  • These novel oligomycins represent promising candidates for cancer chemotherapeutics, particularly for K-Ras-driven cancers.

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